subject:(drug metabolism)

University of Manchester

1. Sall, Carolina. In Vitro-In Vivo Assessment of Repaglinide Metabolism and Drug-Drug Interactions:Towards a Physiologically-Based Pharmacokinetic Model.

Degree: 2013, University of Manchester

URL: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:201277

► Repaglinide is currently recommended as an in vivo CYP2C8 probe by the U.S. Food and Drug Administration (FDA), but the kinetic characterisation and enzymes involved… (more)

▼ Repaglinide is currently recommended as an in vivo CYP2C8 probe by the U.S. Food and Drug Administration (FDA), but the kinetic characterisation and enzymes involved in the elimination of this drug have not been fully delineated. In addition to its complex metabolism, polymorphism in the SLCO1B1 gene encoding for the hepatic uptake transporter organic anion transporting polypeptide 1B1 (OATP1B1) has been shown to impact repaglinide pharmacokinetics, further complicating the prediction of repaglinide clearance and drug-drug interactions (DDIs). The aim of this thesis was to firstly perform a systematic analysis of repaglinide metabolic pathways and thereby assess the contribution of specific enzymes to its clearance, and to secondly increase the understanding of repaglinide as a victim drug by implementing obtained in vitro metabolism data together with reported hepatic uptake parameters into a physiologically-based pharmacokinetic (PBPK) model. Furthermore, reported repaglinide DDIs, repaglinide AUC in different SLCO1B1 genotype groups and repaglinide P450 metabolite ratios were collated and critically analysed.The metabolism of repaglinide was characterised using a range of in vitro systems, namely pooled cryopreserved human hepatocytes, human liver microsomes (HLMs), human S9 fractions and recombinant P450 enzymes. The impact of in vitro systems on the analysis of repaglinide metabolic pathway was investigated and the importance of individual metabolic pathways studied. Definite differences in formation clearance ratios were found between CYP3A4 and CYP2C8 for the formation of M1 and M4 metabolites, resulting in a 60- and 0.05-fold M1:M4 ratio in recombinant CYP3A4 and CYP2C8, respectively. A major system difference was seen in clearances for the formation of M2, which is suggested to be a main metabolite of repaglinide in vivo. An approximately 7-fold higher unbound intrinsic clearance was observed in hepatocytes and S9 fractions in comparison to microsomes; the involvement of aldehyde dehydrogenase in M2 formation was shown for the first time. This systematic analysis revealed a comparable in vitro contribution from CYP2C8 and CYP3A4 to the metabolism of repaglinide (<50%), whereas the contribution of glucuronidation ranged from 2 to 20%, depending on the in vitro system and conditions used. The repaglinide M4 metabolic pathway was proposed as a specific CYP2C8 probe for the assessment of DDIs.A whole-body PBPK repaglinide model was developed in Matlab v.7.10 incorporating multiple eliminations pathways, active uptake and bidirectional passive diffusion together with drug- and system-specific parameters. A considerable clearance underprediction was initially observed after implementation of uptake parameters reported in vitro; empirical uptake scaling factors per SLCO1B1 genotype group were required for accurate prediction of repaglinide in vivo clearance. Furthermore, collated and weighted repaglinide AUC ratios in different genotype groups reflected differences seen for empirical uptake scaling factors… Advisors/Committee Members: HOUSTON, JAMES JB, Houston, James, Galetin, Aleksandra.

Subjects/Keywords: repaglinide; drug metabolism

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APA (6^th Edition):

Sall, C. (2013). In Vitro-In Vivo Assessment of Repaglinide Metabolism and Drug-Drug Interactions:Towards a Physiologically-Based Pharmacokinetic Model. (Doctoral Dissertation). University of Manchester. Retrieved from http://www.manchester.ac.uk/escholar/uk-ac-man-scw:201277

Chicago Manual of Style (16^th Edition):

Sall, Carolina. “In Vitro-In Vivo Assessment of Repaglinide Metabolism and Drug-Drug Interactions:Towards a Physiologically-Based Pharmacokinetic Model.” 2013. Doctoral Dissertation, University of Manchester. Accessed January 23, 2021. http://www.manchester.ac.uk/escholar/uk-ac-man-scw:201277.

MLA Handbook (7^th Edition):

Sall, Carolina. “In Vitro-In Vivo Assessment of Repaglinide Metabolism and Drug-Drug Interactions:Towards a Physiologically-Based Pharmacokinetic Model.” 2013. Web. 23 Jan 2021.

Vancouver:

Sall C. In Vitro-In Vivo Assessment of Repaglinide Metabolism and Drug-Drug Interactions:Towards a Physiologically-Based Pharmacokinetic Model. [Internet] [Doctoral dissertation]. University of Manchester; 2013. [cited 2021 Jan 23]. Available from: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:201277.

Council of Science Editors:

Sall C. In Vitro-In Vivo Assessment of Repaglinide Metabolism and Drug-Drug Interactions:Towards a Physiologically-Based Pharmacokinetic Model. [Doctoral Dissertation]. University of Manchester; 2013. Available from: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:201277

University of Manchester

2. Wood, Francesca Leanne. Optimisation of In Vitro Methodology for Drug Metabolism Studies to Improve Prediction of Hepatic Drug Clearance.

Degree: 2016, University of Manchester

URL: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:301576

► As a critical parameter in pharmacokinetics, prediction of clearance is an integral aspect of drug discovery programmes. Since the liver is the major site of… (more)

▼ As a critical parameter in pharmacokinetics, prediction of clearance is an integral aspect of drug discovery programmes. Since the liver is the major site of xenobiotic biotransformation, accurate prediction of hepatic clearance (CLh) is vital. The use of cellular and subcellular in vitro systems for this purpose is common practice; however, prediction accuracy tends to be poor. The aim of this thesis was to explore potential contributing factors to the underprediction of in vivo clearance, specifically with relation to the in vitro methodology of hepatocyte clearance assays, which is largely unstandardised.Literature data analyses highlighted an overall clearance-dependent trend of underprediction in both human and rat hepatocytes, indicating a fundamental in vitro system bias which is independent of species. During initial investigation of incubation conditions, the format of hepatocyte assays (suspension in microcentrifuge tubes, 96-well plates, 24-well plates and short-term monolayer culture) was demonstrated to influence determined intrinsic clearance (CLint). Differences in midazolam CLint were observed not only between suspended and short-term cultured hepatocytes, but also between suspended hepatocytes in different vessels/plate formats. The applicability of 1 µM as a generic substrate incubation concentration for determination of CLint by substrate depletion was evaluated in rat hepatocytes using nine well-characterised drugs. For seven of the nine drugs, a statistically significantly (p < 0.05) higher CLint was observed in determinations of 0.1 µM substrate as opposed to 1 µM, highlighting the potential for false determinations using current practices.Cofactor depletion in isolated hepatocytes was investigated based on previous speculation as the cause of clearance-dependent underprediction of in vivo clearance. Although moderate increases in CLint were observed with the addition of NADPH to hepatocyte incubations, this was subsequently attributed to the replenishment of NADPH in membrane-damaged hepatocytes. Retained functionality of metabolic enzymes in cells which would generally be considered non-viable by trypan blue exclusion was indicated in comparisons of unpurified and Percoll-purified cryopreserved hepatocytes. This phenomenon was conclusively demonstrated in incubations of permeabilised hepatocytes supplemented with NADPH, revealing a need for re-evaluation of the use of plasma membrane integrity (trypan blue exclusion) as a measure of viability in metabolic studies. ATP content was considered as a potential alternative measure; however no significant correlations were found between ATP content, trypan blue exclusion and the CLint of nine drugs in associated preparations.The effect of shaking on CLint in rat hepatocytes was also examined. For 10 out of 12 drugs, CLint determined at 900 rpm was significantly (p < 0.05) higher than in static incubations. Three potential mechanisms were hypothesised: plasma membrane damage, increased substrate distribution throughout the bulk medium and reduction in… Advisors/Committee Members: HALLIFAX, DAVID D, Houston, James, Hallifax, David.

Subjects/Keywords: hepatocytes; hepatic clearance; drug metabolism

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APA (6^th Edition):

Wood, F. L. (2016). Optimisation of In Vitro Methodology for Drug Metabolism Studies to Improve Prediction of Hepatic Drug Clearance. (Doctoral Dissertation). University of Manchester. Retrieved from http://www.manchester.ac.uk/escholar/uk-ac-man-scw:301576

Chicago Manual of Style (16^th Edition):

Wood, Francesca Leanne. “Optimisation of In Vitro Methodology for Drug Metabolism Studies to Improve Prediction of Hepatic Drug Clearance.” 2016. Doctoral Dissertation, University of Manchester. Accessed January 23, 2021. http://www.manchester.ac.uk/escholar/uk-ac-man-scw:301576.

MLA Handbook (7^th Edition):

Wood, Francesca Leanne. “Optimisation of In Vitro Methodology for Drug Metabolism Studies to Improve Prediction of Hepatic Drug Clearance.” 2016. Web. 23 Jan 2021.

Vancouver:

Wood FL. Optimisation of In Vitro Methodology for Drug Metabolism Studies to Improve Prediction of Hepatic Drug Clearance. [Internet] [Doctoral dissertation]. University of Manchester; 2016. [cited 2021 Jan 23]. Available from: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:301576.

Council of Science Editors:

Wood FL. Optimisation of In Vitro Methodology for Drug Metabolism Studies to Improve Prediction of Hepatic Drug Clearance. [Doctoral Dissertation]. University of Manchester; 2016. Available from: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:301576

University of Toronto

3. Utgikar, Rucha. Down-regulation of Cytochrome P450 2C8 by 3-methylcholanthrene in Human Hepatocellualar Carcinoma Cell Lines.

Degree: 2012, University of Toronto

URL: http://hdl.handle.net/1807/32636

►

3-Methylcholanthrene (MC) is a model polycyclic aromatic hydrocarbon that induces cytochrome P450 1A1 (CYP1A1) expression. This laboratory has shown previously that aromatic hydrocarbons, which are… (more)

Subjects/Keywords: drug metabolism; CYP2C8; 0419

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APA (6^th Edition):

Utgikar, R. (2012). Down-regulation of Cytochrome P450 2C8 by 3-methylcholanthrene in Human Hepatocellualar Carcinoma Cell Lines. (Masters Thesis). University of Toronto. Retrieved from http://hdl.handle.net/1807/32636

Chicago Manual of Style (16^th Edition):

Utgikar, Rucha. “Down-regulation of Cytochrome P450 2C8 by 3-methylcholanthrene in Human Hepatocellualar Carcinoma Cell Lines.” 2012. Masters Thesis, University of Toronto. Accessed January 23, 2021. http://hdl.handle.net/1807/32636.

MLA Handbook (7^th Edition):

Utgikar, Rucha. “Down-regulation of Cytochrome P450 2C8 by 3-methylcholanthrene in Human Hepatocellualar Carcinoma Cell Lines.” 2012. Web. 23 Jan 2021.

Vancouver:

Utgikar R. Down-regulation of Cytochrome P450 2C8 by 3-methylcholanthrene in Human Hepatocellualar Carcinoma Cell Lines. [Internet] [Masters thesis]. University of Toronto; 2012. [cited 2021 Jan 23]. Available from: http://hdl.handle.net/1807/32636.

Council of Science Editors:

Utgikar R. Down-regulation of Cytochrome P450 2C8 by 3-methylcholanthrene in Human Hepatocellualar Carcinoma Cell Lines. [Masters Thesis]. University of Toronto; 2012. Available from: http://hdl.handle.net/1807/32636

4. Koppel, Nitzan. Characterization of a widely distributed cardiac drug-inactivating enzyme from the human gut bacterium Eggerthella lenta.

Degree: PhD, 2018, Harvard University

URL: http://nrs.harvard.edu/urn-3:HUL.InstRepos:41129160

► The human body is colonized by trillions of microorganisms that are increasingly implicated in modulating human health and disease. In particular, the human gut microbiota… (more)

▼ The human body is colonized by trillions of microorganisms that are increasingly implicated in modulating human health and disease. In particular, the human gut microbiota is involved in the metabolism of over fifty pharmaceuticals, yielding metabolites with altered biological properties and toxicities. It has been known for decades that particular isolates of the human gut bacterium Eggerthella lenta transform the plant-derived toxin and cardiac drug digoxin into the inactive metabolite (20R)-dihydrodigoxin, leading to decreased efficacy in a considerable subset of patients. Recently, the Turnbaugh lab identified the cardiac glycoside reductase (cgr) operon, a digoxin-inducible gene cluster that was predicted to be responsible for digoxin metabolism. In this thesis, we sought to expand our mechanistic understanding of this clinically relevant transformation and investigate its broader implications for gut microbial and human health. Through heterologous expression and in vitro biochemical characterization, we discovered that the E. lenta enzyme Cgr2 is sufficient for digoxin reduction and inactivation. Having validated the cgr2 gene as a biomarker for digoxin reduction, we probed the distribution of this metabolism among E. lenta strains and in the general human population. Using culturing and sequencing analyses, we identified seven additional digoxin-metabolizing strains of E. lenta with remarkable sequence conservation of the cgr2 gene (>98% sequence identity). Metagenomic and qRT-PCR analyses confirmed the high sequence conservation of the cgr2 gene and revealed that cgr2+ E. lenta are widespread, but often low in abundance in the human gut microbiota. We next probed the biochemical mechanism of digoxin reduction by the prevalent Cgr2 enzyme. Using a combination of biochemical, bioinformatic, and spectroscopic techniques, we determined that Cgr2 is a unique reductase that requires an FAD cofactor, harbors oxygen-sensitive, redox-active [4Fe-4S] clusters, and may contain a divalent metal cation center. Although the presence of [4Fe-4S] clusters in Cgr2 was unexpected, these metalloclusters proved to be essential for Cgr2 stability and likely serve a catalytic, electron transfer role. We further identified six cysteine residues that are important for Cgr2 activity and may influence metallocofactor binding. We next explored the evolutionary origins and impacts of digoxin metabolism on E. lenta. Despite the high sequence conservation of the cgr operon, no obvious physiological benefit (e.g. growth advantage) could be linked to this metabolism. We thus investigated whether digoxin is the endogenous substrate of Cgr2 by assessing the activity of this enzyme toward a panel of alternative candidate substrates that may be relevant in the gut. However, Cgr2 metabolism appears to be restricted to digoxin and highly similar cardenolide toxins produced by plants. We thus propose that the cgr pathway may have evolved to protect humans from ingested toxins in an analogous manner to host xenobiotic-detoxifying enzymes. By… Advisors/Committee Members: Balskus, Emily (advisor), Liu, David R. (committee member), Pandelia, Maria-Eirini (committee member).

Subjects/Keywords: Gut microbiota; drug metabolism; biochemistry

10 more images…

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Koppel, N. (2018). Characterization of a widely distributed cardiac drug-inactivating enzyme from the human gut bacterium Eggerthella lenta. (Doctoral Dissertation). Harvard University. Retrieved from http://nrs.harvard.edu/urn-3:HUL.InstRepos:41129160

Chicago Manual of Style (16^th Edition):

Koppel, Nitzan. “Characterization of a widely distributed cardiac drug-inactivating enzyme from the human gut bacterium Eggerthella lenta.” 2018. Doctoral Dissertation, Harvard University. Accessed January 23, 2021. http://nrs.harvard.edu/urn-3:HUL.InstRepos:41129160.

MLA Handbook (7^th Edition):

Koppel, Nitzan. “Characterization of a widely distributed cardiac drug-inactivating enzyme from the human gut bacterium Eggerthella lenta.” 2018. Web. 23 Jan 2021.

Vancouver:

Koppel N. Characterization of a widely distributed cardiac drug-inactivating enzyme from the human gut bacterium Eggerthella lenta. [Internet] [Doctoral dissertation]. Harvard University; 2018. [cited 2021 Jan 23]. Available from: http://nrs.harvard.edu/urn-3:HUL.InstRepos:41129160.

Council of Science Editors:

Koppel N. Characterization of a widely distributed cardiac drug-inactivating enzyme from the human gut bacterium Eggerthella lenta. [Doctoral Dissertation]. Harvard University; 2018. Available from: http://nrs.harvard.edu/urn-3:HUL.InstRepos:41129160

University of Manchester

5. Sall, Carolina. In vitro-in vivo assessment of repaglinide metabolism and drug-drug interactions : towards a physiologically-based pharmacokinetic model.

Degree: PhD, 2013, University of Manchester

URL: https://www.research.manchester.ac.uk/portal/en/theses/in-vitroin-vivo-assessment-of-repaglinide-metabolism-and-drugdrug-interactionstowards-a-physiologicallybased-pharmacokinetic-model(1b8eca49-bc68-484e-b921-2e324b4c5f00).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.756781

► Repaglinide is currently recommended as an in vivo CYP2C8 probe by the U.S. Food and Drug Administration (FDA), but the kinetic characterisation and enzymes involved… (more)

▼ Repaglinide is currently recommended as an in vivo CYP2C8 probe by the U.S. Food and Drug Administration (FDA), but the kinetic characterisation and enzymes involved in the elimination of this drug have not been fully delineated. In addition to its complex metabolism, polymorphism in the SLCO1B1 gene encoding for the hepatic uptake transporter organic anion transporting polypeptide 1B1 (OATP1B1) has been shown to impact repaglinide pharmacokinetics, further complicating the prediction of repaglinide clearance and drug-drug interactions (DDIs). The aim of this thesis was to firstly perform a systematic analysis of repaglinide metabolic pathways and thereby assess the contribution of specific enzymes to its clearance, and to secondly increase the understanding of repaglinide as a victim drug by implementing obtained in vitro metabolism data together with reported hepatic uptake parameters into a physiologically-based pharmacokinetic (PBPK) model. Furthermore, reported repaglinide DDIs, repaglinide AUC in different SLCO1B1 genotype groups and repaglinide P450 metabolite ratios were collated and critically analysed. The metabolism of repaglinide was characterised using a range of in vitro systems, namely pooled cryopreserved human hepatocytes, human liver microsomes (HLMs), human S9 fractions and recombinant P450 enzymes. The impact of in vitro systems on the analysis of repaglinide metabolic pathway was investigated and the importance of individual metabolic pathways studied. Definite differences in formation clearance ratios were found between CYP3A4 and CYP2C8 for the formation of M1 and M4 metabolites, resulting in a 60- and 0.05-fold M1:M4 ratio in recombinant CYP3A4 and CYP2C8, respectively. A major system difference was seen in clearances for the formation of M2, which is suggested to be a main metabolite of repaglinide in vivo. An approximately 7-fold higher unbound intrinsic clearance was observed in hepatocytes and S9 fractions in comparison to microsomes; the involvement of aldehyde dehydrogenase in M2 formation was shown for the first time. This systematic analysis revealed a comparable in vitro contribution from CYP2C8 and CYP3A4 to the metabolism of repaglinide.

Subjects/Keywords: 610; repaglinide; drug metabolism

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APA (6^th Edition):

Sall, C. (2013). In vitro-in vivo assessment of repaglinide metabolism and drug-drug interactions : towards a physiologically-based pharmacokinetic model. (Doctoral Dissertation). University of Manchester. Retrieved from https://www.research.manchester.ac.uk/portal/en/theses/in-vitroin-vivo-assessment-of-repaglinide-metabolism-and-drugdrug-interactionstowards-a-physiologicallybased-pharmacokinetic-model(1b8eca49-bc68-484e-b921-2e324b4c5f00).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.756781

Chicago Manual of Style (16^th Edition):

Sall, Carolina. “In vitro-in vivo assessment of repaglinide metabolism and drug-drug interactions : towards a physiologically-based pharmacokinetic model.” 2013. Doctoral Dissertation, University of Manchester. Accessed January 23, 2021. https://www.research.manchester.ac.uk/portal/en/theses/in-vitroin-vivo-assessment-of-repaglinide-metabolism-and-drugdrug-interactionstowards-a-physiologicallybased-pharmacokinetic-model(1b8eca49-bc68-484e-b921-2e324b4c5f00).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.756781.

MLA Handbook (7^th Edition):

Sall, Carolina. “In vitro-in vivo assessment of repaglinide metabolism and drug-drug interactions : towards a physiologically-based pharmacokinetic model.” 2013. Web. 23 Jan 2021.

Vancouver:

Sall C. In vitro-in vivo assessment of repaglinide metabolism and drug-drug interactions : towards a physiologically-based pharmacokinetic model. [Internet] [Doctoral dissertation]. University of Manchester; 2013. [cited 2021 Jan 23]. Available from: https://www.research.manchester.ac.uk/portal/en/theses/in-vitroin-vivo-assessment-of-repaglinide-metabolism-and-drugdrug-interactionstowards-a-physiologicallybased-pharmacokinetic-model(1b8eca49-bc68-484e-b921-2e324b4c5f00).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.756781.

Council of Science Editors:

Sall C. In vitro-in vivo assessment of repaglinide metabolism and drug-drug interactions : towards a physiologically-based pharmacokinetic model. [Doctoral Dissertation]. University of Manchester; 2013. Available from: https://www.research.manchester.ac.uk/portal/en/theses/in-vitroin-vivo-assessment-of-repaglinide-metabolism-and-drugdrug-interactionstowards-a-physiologicallybased-pharmacokinetic-model(1b8eca49-bc68-484e-b921-2e324b4c5f00).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.756781

Rice University

6. Mitchell, Nicole Elyse. Machine Learning-Based Prediction of Sites of Metabolism in Drugs: Exploring Feature Extraction Methods on Molecular Graphs.

Degree: MS, Engineering, 2020, Rice University

URL: http://hdl.handle.net/1911/108430

► Drug metabolism studies are a critical component of the drug design process. Metabolism of some drugs can lead to diminished therapeutic efficacy or even toxicity.… (more)

▼ Drug metabolism studies are a critical component of the drug design process. Metabolism of some drugs can lead to diminished therapeutic efficacy or even toxicity. The stability of a drug is expressed by the atoms, called Sites of Metabolism (SOMs), which undergo structural changes when that drug interacts with a metabolizing enzyme. Computationally predicting these metabolically labile atoms early on in the drug development process will enable pharmaceutical chemists to design molecules with favorable metabolic properties. A number of in silico methods have been developed for identifying SOMs, with a recent focus on machine learning due to its computational efficiency over structural modeling. Machine learning techniques classify atoms as SOMs based on feature vector representations. Existing approaches rely upon expert knowledge and often expensive experiments to engineer fixed atom descriptors with extensive sets of experimentally-derived attributes. However, models based upon learned instead of fixed representations have proven promising in other chemoinformatics tasks. Seeing molecules as attributed graphs, where atoms correspond to nodes and bonds correspond to edges, the SOM prediction problem can be formulated as a node classification task. We compare two methods of extracting node features from molecular graphs: a standard fingerprint generation strategy used by existing SOM prediction methods, which constructs task-agnostic node descriptors; and an unexplored approach based on a graph convolutional neural network, which learns task-specific node encodings. Both methods take into account the node attributes and graph connectivity to generate descriptive atom representations. We experiment with factors that can influence the performance of both feature extraction methods on a dataset commonly used in the literature for predicting SOMs. Despite the fact that the graph convolution approach requires more data and has more parameters to tune, we have achieved comparable performance between the two methods. Given enough data, we believe the graph convolution approach may reliably achieve improved performance over the fingerprint generation strategy. Our results indicate that the graph convolution approach can outperform the fixed fingerprint generation strategy when starting from molecular graphs that are not initialized with rich electro-chemical properties, demonstrating how learned representations could replace the need for expert-derived features for SOM prediction. Our results also illustrate the importance of tuning the feature extraction method to the metabolizing enzyme of interest. Advisors/Committee Members: Kavraki, Lydia E (advisor).

Subjects/Keywords: machine learning; drug metabolism

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APA (6^th Edition):

Mitchell, N. E. (2020). Machine Learning-Based Prediction of Sites of Metabolism in Drugs: Exploring Feature Extraction Methods on Molecular Graphs. (Masters Thesis). Rice University. Retrieved from http://hdl.handle.net/1911/108430

Chicago Manual of Style (16^th Edition):

Mitchell, Nicole Elyse. “Machine Learning-Based Prediction of Sites of Metabolism in Drugs: Exploring Feature Extraction Methods on Molecular Graphs.” 2020. Masters Thesis, Rice University. Accessed January 23, 2021. http://hdl.handle.net/1911/108430.

MLA Handbook (7^th Edition):

Mitchell, Nicole Elyse. “Machine Learning-Based Prediction of Sites of Metabolism in Drugs: Exploring Feature Extraction Methods on Molecular Graphs.” 2020. Web. 23 Jan 2021.

Vancouver:

Mitchell NE. Machine Learning-Based Prediction of Sites of Metabolism in Drugs: Exploring Feature Extraction Methods on Molecular Graphs. [Internet] [Masters thesis]. Rice University; 2020. [cited 2021 Jan 23]. Available from: http://hdl.handle.net/1911/108430.

Council of Science Editors:

Mitchell NE. Machine Learning-Based Prediction of Sites of Metabolism in Drugs: Exploring Feature Extraction Methods on Molecular Graphs. [Masters Thesis]. Rice University; 2020. Available from: http://hdl.handle.net/1911/108430

University of Arizona

7. Fan, Xiaoyu. Function and Regulation of Intestinal Cytochrome P450 .

Degree: 2019, University of Arizona

URL: http://hdl.handle.net/10150/634254

► The overall goal of this thesis was to study the function and regulation of intestinal P450s. The central hypothesis is that disease state and environmental… (more)

▼ The overall goal of this thesis was to study the function and regulation of intestinal P450s. The central hypothesis is that disease state and environmental pollutant exposure will impact intestinal P450 expression and P450-mediated drug metabolism and alter the bioavailability of orally administered drugs. The specific aims are: 1) to determine whether metabolism by microsomal P450 enzymes in intestine and liver influences the bioavailability of niclosamide, which is a repurposed drug with multiple new therapeutic effects; 2) to examine whether intestinal inflammation will impact expression and activity of intestinal P450s and whether the impact will cause any change in drug pharmacokinetics; 3) to determine the impact of oral arsenic exposure on hepatic and intestinal P450s and P450-mediated drug metabolism. In the first aim (Chapter 2), we have determined whether metabolic disposition by microsomal P450 enzymes in liver and intestine influences niclosamide’s bioavailability in vivo, by comparing niclosamide metabolism in wild-type, liver-Cpr-null (LCN), and intestinal epithelium-Cpr-null (IECN) mice. In vitro stability of niclosamide in microsomal incubations was greater in the intestine than in liver in the presence of NADPH, but it was much greater in liver than in intestine in the presence of UDPGA. NADPH-dependent niclosamide disposition and hydroxy-niclosamide formation were inhibited in LCN mice due to suppressed hepatic P450 activities, but not changed in IECN mice which had suppressed intestinal P450 activities. In intestinal microsomal reactions, hydroxy-niclosamide formation was not detected; but rates of niclosamide-glucuronide formation were greater than in liver of mice. Pharmacokinetic profiles of oral niclosamide were only minimally changed in LCN mice. The changes seem to reflect the compensatory increase in hepatic UDP-glucuronosyltransferase activity. These results suggest that efforts to increase the bioavailability of niclosamide by blocking its metabolism by P450 enzymes unlikely to be fruitful. In contrast, inhibition of niclosamide glucuronidation in both liver and intestine may prove effective for increasing niclosamide’s bioavailability, thereby making it practical to repurpose this drug for treating systemic diseases. In the second aim (Chapter 3), we have determined the impact of intestinal inflammation on the expression of intestinal P450s by using a dextran sulfate sodium salt (DSS)-induced colitis mouse model. Several P450 enzymes were down-regulated at both the mRNA level and the protein level. The in vitro metabolic activities of CYP3A and CYP2C, assayed using diclofenac and nifedipine as substrates, were reduced in intestinal microsomes prepared from mice treated with DSS than in control mice. Several transporters, including both uptake and efflux transporters, were also down-regulated at the mRNA levels. Pharmacokinetic analyses using nifedipine, lovastatin, pravastatin, and cyclosporine A indicated that the extent of impact of DSS treatment on in vivo clearance is drug… Advisors/Committee Members: Zhang, Qing-Yu (advisor), Ding, Xinxin (committeemember), Cherrington, Nathan J. (committeemember), Zhang, Donna (committeemember), Klimecki, Walter T. (committeemember).

Subjects/Keywords: Drug metabolism; Intestinal P450s

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APA (6^th Edition):

Fan, X. (2019). Function and Regulation of Intestinal Cytochrome P450 . (Doctoral Dissertation). University of Arizona. Retrieved from http://hdl.handle.net/10150/634254

Chicago Manual of Style (16^th Edition):

Fan, Xiaoyu. “Function and Regulation of Intestinal Cytochrome P450 .” 2019. Doctoral Dissertation, University of Arizona. Accessed January 23, 2021. http://hdl.handle.net/10150/634254.

MLA Handbook (7^th Edition):

Fan, Xiaoyu. “Function and Regulation of Intestinal Cytochrome P450 .” 2019. Web. 23 Jan 2021.

Vancouver:

Fan X. Function and Regulation of Intestinal Cytochrome P450 . [Internet] [Doctoral dissertation]. University of Arizona; 2019. [cited 2021 Jan 23]. Available from: http://hdl.handle.net/10150/634254.

Council of Science Editors:

Fan X. Function and Regulation of Intestinal Cytochrome P450 . [Doctoral Dissertation]. University of Arizona; 2019. Available from: http://hdl.handle.net/10150/634254

University of Toronto

8. Novalen, Maria. Investigation of a Metabolic Pathway Leading to an Idiosyncratic Drug Reaction: Is the Sulfate of 12-Hydroxynevirapine Responsible for the Skin Rash in Brown Norway rats?.

Degree: 2010, University of Toronto

URL: http://hdl.handle.net/1807/25882

►

An animal model of nevirapine (NVP)-induced skin rash was used to test the hypothesis that sulfonation of 12-OH NVP, a metabolite of NVP proven essential… (more)

Subjects/Keywords: nevirapine; drug metabolism; adverse drug reactions; idiosyncratic drug reactions; 0383

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APA (6^th Edition):

Novalen, M. (2010). Investigation of a Metabolic Pathway Leading to an Idiosyncratic Drug Reaction: Is the Sulfate of 12-Hydroxynevirapine Responsible for the Skin Rash in Brown Norway rats?. (Masters Thesis). University of Toronto. Retrieved from http://hdl.handle.net/1807/25882

Chicago Manual of Style (16^th Edition):

Novalen, Maria. “Investigation of a Metabolic Pathway Leading to an Idiosyncratic Drug Reaction: Is the Sulfate of 12-Hydroxynevirapine Responsible for the Skin Rash in Brown Norway rats?.” 2010. Masters Thesis, University of Toronto. Accessed January 23, 2021. http://hdl.handle.net/1807/25882.

MLA Handbook (7^th Edition):

Novalen, Maria. “Investigation of a Metabolic Pathway Leading to an Idiosyncratic Drug Reaction: Is the Sulfate of 12-Hydroxynevirapine Responsible for the Skin Rash in Brown Norway rats?.” 2010. Web. 23 Jan 2021.

Vancouver:

Novalen M. Investigation of a Metabolic Pathway Leading to an Idiosyncratic Drug Reaction: Is the Sulfate of 12-Hydroxynevirapine Responsible for the Skin Rash in Brown Norway rats?. [Internet] [Masters thesis]. University of Toronto; 2010. [cited 2021 Jan 23]. Available from: http://hdl.handle.net/1807/25882.

Council of Science Editors:

Novalen M. Investigation of a Metabolic Pathway Leading to an Idiosyncratic Drug Reaction: Is the Sulfate of 12-Hydroxynevirapine Responsible for the Skin Rash in Brown Norway rats?. [Masters Thesis]. University of Toronto; 2010. Available from: http://hdl.handle.net/1807/25882

Vanderbilt University

9. Baglia, Michelle Lynn. Germline and Somatic Variation in Genes Involved in Metabolism of Chemotherapy Drugs and Breast Cancer Outcomes.

Degree: PhD, Epidemiology, 2016, Vanderbilt University

URL: http://hdl.handle.net/1803/10714

► Triple-negative breast cancer (TNBC), which is characterized by minimal or lack of expression of estrogen receptors and progesterone receptors, and the absence of overexpression of… (more)

▼ Triple-negative breast cancer (TNBC), which is characterized by minimal or lack of expression of estrogen receptors and progesterone receptors, and the absence of overexpression of human epidermal growth factor 2 (ER-/PR-/HER2-), makes up 15%-20% of breast cancers in the United States. Although there have been recent advances in breast cancer detection/treatment leading to improved survival overall, the prognosis for TNBC patients is much worse compared to other breast cancer types. Chemotherapy is the standard treatment for TNBC patients but patient response to treatment varies tremendously. Understanding the underlying molecular biological mechanisms is critical to improve outcomes for this group of aggressive breast cancers. Using resources available from the Shanghai Breast Cancer Survival Study, we evaluated the association between germline and somatic variation in chemotherapy metabolizing genes and breast cancer outcomes. Our study focused on genes involved in the metabolism of cyclophosphamide and 5-fluorouracil, the two most commonly used chemotherapy agents in our study population. Using a gene score approach, we evaluated the separate and joint association of germline polymorphisms and tumor-level gene expression with disease-free survival (DFS) and overall survival (OS) using Cox models. No association between the cyclophosphamide polymorphism score and DFS or OS was observed. The 5-fluorouracil polymorphism score was associated with marginally improved OS, particularly among those who took 5-fluorouracil. The cyclophosphamide gene expression score was associated with OS among all participants for events occurring in the first three years following breast cancer diagnosis. The 5-fluorouracil gene expression score was associated with worse DFS among all participants for events occurring in the first three years following cancer diagnosis. No association was observed for the joint effect of the polymorphism score and the gene expression score for either chemotherapy drug. However, our study had a low statistical power to investigate the joint effect. Future studies with larger sample size are needed to further elucidate the roles of genes involved in the pathways by which chemotherapy drugs are metabolized to understand the biology of chemotherapy responses. Advisors/Committee Members: Fei Ye (committee member), Sarah Nechuta (committee member), Jirong Long (committee member), Xiao-Ou Shu (Committee Chair).

Subjects/Keywords: chemotherapy; drug metabolism; survival; breast cancer

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Baglia, M. L. (2016). Germline and Somatic Variation in Genes Involved in Metabolism of Chemotherapy Drugs and Breast Cancer Outcomes. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/10714

Chicago Manual of Style (16^th Edition):

Baglia, Michelle Lynn. “Germline and Somatic Variation in Genes Involved in Metabolism of Chemotherapy Drugs and Breast Cancer Outcomes.” 2016. Doctoral Dissertation, Vanderbilt University. Accessed January 23, 2021. http://hdl.handle.net/1803/10714.

MLA Handbook (7^th Edition):

Baglia, Michelle Lynn. “Germline and Somatic Variation in Genes Involved in Metabolism of Chemotherapy Drugs and Breast Cancer Outcomes.” 2016. Web. 23 Jan 2021.

Vancouver:

Baglia ML. Germline and Somatic Variation in Genes Involved in Metabolism of Chemotherapy Drugs and Breast Cancer Outcomes. [Internet] [Doctoral dissertation]. Vanderbilt University; 2016. [cited 2021 Jan 23]. Available from: http://hdl.handle.net/1803/10714.

Council of Science Editors:

Baglia ML. Germline and Somatic Variation in Genes Involved in Metabolism of Chemotherapy Drugs and Breast Cancer Outcomes. [Doctoral Dissertation]. Vanderbilt University; 2016. Available from: http://hdl.handle.net/1803/10714

Texas A&M University

10. Liu, Zhen. Understanding and Targeting Lipid Metabolism of Mycobacterium tuberculosis.

Degree: PhD, Chemistry, 2013, Texas A&M University

URL: http://hdl.handle.net/1969.1/151650

► Mycobacterium tuberculosis (M. tuberculosis) contains a wide array of genes responsible for the synthesis and secretion of a variety of bioactive lipids. The genes represent… (more)

▼ Mycobacterium tuberculosis (M. tuberculosis) contains a wide array of genes responsible for the synthesis and secretion of a variety of bioactive lipids. The genes represent attractive drug-targets due to their involvement in essential cell cycles, the implication in pathogenesis, and the interference with therapeutics. In this thesis, I report our efforts to understand the biological functions of, and to develop inhibitors against, multiple genes related to M. tuberculosis lipid metabolism. Firstly, dioctylamine, a substrate mimic of the mycolic acid cyclopropane synthases, is shown to inhibit CmaA2 in vitro. Its inhibition action is explained by the structural characterization. Together with our collaborators, we have found dioctylamine able to intervene multiple mycolic acid cyclopropane synthases in vivo, and hence established the first model study for the single-drug-multiple-target strategy to inhibit the mycolic acid biosynthesis of M. tuberculosis. In addition, dioctylamine can serve as the platform for the design of more potent and selective drugs in the future. Secondly, the action mechanism of isoniazid and ethionamide, both of which are pro-drugs targeting the mycolic acid biosynthesis, is explored via biochemical, X-ray crystallographic or modeling studies. We have determined that the intracellular target of isoniazid is the enoyl reductase InhA; and we have discovered the correlation between mycothiol and ethionamide susceptibility. Thirdly, I have investigated the function and mechanism of FadD10, an enzyme involved in the synthesis of a virulence-related lipopeptide. The results reveal that FadD10 was mis-annotated as a fatty acyl-CoA ligase, but it indeed transfers fatty acids to an acyl carrier protein (Rv0100). Further crystallographic characterization provides the molecular basis for the mechanism of FadD10, leading to the discovery of a new type of adenylate-forming enzyme. Advisors/Committee Members: Sacchettini, James C. (advisor), Barondeau, David (committee member), Burgess, Kevin (committee member), Igumenova, Tatyana (committee member).

Subjects/Keywords: Structural biology; Enzymology; Drug discovery; Lipid metabolism

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APA (6^th Edition):

Liu, Z. (2013). Understanding and Targeting Lipid Metabolism of Mycobacterium tuberculosis. (Doctoral Dissertation). Texas A&M University. Retrieved from http://hdl.handle.net/1969.1/151650

Chicago Manual of Style (16^th Edition):

Liu, Zhen. “Understanding and Targeting Lipid Metabolism of Mycobacterium tuberculosis.” 2013. Doctoral Dissertation, Texas A&M University. Accessed January 23, 2021. http://hdl.handle.net/1969.1/151650.

MLA Handbook (7^th Edition):

Liu, Zhen. “Understanding and Targeting Lipid Metabolism of Mycobacterium tuberculosis.” 2013. Web. 23 Jan 2021.

Vancouver:

Liu Z. Understanding and Targeting Lipid Metabolism of Mycobacterium tuberculosis. [Internet] [Doctoral dissertation]. Texas A&M University; 2013. [cited 2021 Jan 23]. Available from: http://hdl.handle.net/1969.1/151650.

Council of Science Editors:

Liu Z. Understanding and Targeting Lipid Metabolism of Mycobacterium tuberculosis. [Doctoral Dissertation]. Texas A&M University; 2013. Available from: http://hdl.handle.net/1969.1/151650

Texas A&M University

11. Huang, Hsiao-Ling. Structural and Biochemical Studies of Glyoxylate Shunt Enzymes as Drug Targets of Mycobacterium tuberculosis.

Degree: PhD, Chemistry, 2016, Texas A&M University

URL: http://hdl.handle.net/1969.1/174220

► As the world population battles drug-resistant tuberculosis (TB), there is an urgent need for novel anti-tubercular drugs. This dissertation documents the studies of glyoxylate shunt… (more)

▼ As the world population battles drug-resistant tuberculosis (TB), there is an urgent need for novel anti-tubercular drugs. This dissertation documents the studies of glyoxylate shunt enzymes, isocitrate lyase (ICL) and malate synthase (GlcB), in Mycobacterium tuberculosis (Mtb) as drug targets for the therapeutic development of TB. Two different drug discovery approaches were used. A mechanism based approach was utilized for isocitrate lyase, while a fragment based approach was applied for malate synthase, and both approaches employed X-ray crystallography as a primary technique. Through the mechanism based approach, an ICL inhibitor complexed crystal structure was solved to 2.6 Å resolution after the treatment with itaconate. From the structure, the active site cysteine (Cys191) underwent covalent modification to form an S-methylsuccinyl adduct. The inhibitory mechanism was based on the direct nucleophilic attack on the itaconate vinyl group by Cys191 after activation via a nearby general base. Additional crystal structure of ICL following the inactivation by 2-vinyl isocitrate (2-VIC) at 1.8 Å resolution confirmed the formation of an S-homopyruvoyl adduct of Cys191. The structure was consistent with the proposed inhibitory mechanism where 2-VIC first bound in the active site in the same manner as the substrate isocitrate. A base catalyzed aldo cleavage of the C2-C3 bond of 2-VIC then produced 2-vinyl glyoxylate and the aci-succinate. Cys191 was deprotonated to generate succinate, as in the lyase mechanism, followed by the Michael addition of Cys191 thiolate to 2-vinyl glyoxylate to form the final S-homopyruoyl adduct. A fragment based approach was used to advance drug discovery and further probe the active site of Mtb GlcB. Two libraries of 1580 fragments were screened against GlcB using differential scanning fluorimetry (DSF) to identify binding hits, and 18 complexed crystal structures were solved at 1.9-2.5 Å resolutions. The fragment bound GlcB crystal structures captured the conformations of the active site, which have not been reported for Mtb GlcB. The movements of two loops around the active site gave rise to a second portal to the surface and the narrowing of the active site tunnel. This series of conformational changes was hypothesized as a pathway for substrate-product exchange. The structures of the enzyme at various stages of product formation and dissociation, as well as an apo enzyme structure, were further elucidated to confirm the hypothesis. As a result, a detailed, mechanism driven substrate-product exchange in catalysis was formulated. One novel interaction from the fragments and the enzyme was further incorporated into the existing phenyl-diketo acid (PDKA) inhibitor, providing new drug designs. The resulting lead molecule was 100 times more potent compared to the parent PDKA, and was shown to make the same interaction and induce the same movement in the active site as the original fragment. The comprehensive knowledge from the structural studies of the two glyoxylate shunt enzymes provided… Advisors/Committee Members: Sacchettini, James C (advisor), David, Barondeau P (committee member), Pellois, Jean-Philippe (committee member), Meek, Thomas D (committee member).

Subjects/Keywords: Drug Discovery; Structural Biology; Carbon Metabolism; Tuberculosis

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Huang, H. (2016). Structural and Biochemical Studies of Glyoxylate Shunt Enzymes as Drug Targets of Mycobacterium tuberculosis. (Doctoral Dissertation). Texas A&M University. Retrieved from http://hdl.handle.net/1969.1/174220

Chicago Manual of Style (16^th Edition):

Huang, Hsiao-Ling. “Structural and Biochemical Studies of Glyoxylate Shunt Enzymes as Drug Targets of Mycobacterium tuberculosis.” 2016. Doctoral Dissertation, Texas A&M University. Accessed January 23, 2021. http://hdl.handle.net/1969.1/174220.

MLA Handbook (7^th Edition):

Huang, Hsiao-Ling. “Structural and Biochemical Studies of Glyoxylate Shunt Enzymes as Drug Targets of Mycobacterium tuberculosis.” 2016. Web. 23 Jan 2021.

Vancouver:

Huang H. Structural and Biochemical Studies of Glyoxylate Shunt Enzymes as Drug Targets of Mycobacterium tuberculosis. [Internet] [Doctoral dissertation]. Texas A&M University; 2016. [cited 2021 Jan 23]. Available from: http://hdl.handle.net/1969.1/174220.

Council of Science Editors:

Huang H. Structural and Biochemical Studies of Glyoxylate Shunt Enzymes as Drug Targets of Mycobacterium tuberculosis. [Doctoral Dissertation]. Texas A&M University; 2016. Available from: http://hdl.handle.net/1969.1/174220

University of Manchester

12. Cantu Reinhard, Fabian Gilberto. A Computational Chemistry Approach to Cytochrome P450 Metabolism.

Degree: 2018, University of Manchester

URL: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:317301

► Drugs and other xenobiotic compounds exhibit different transformations upon entering the human body, most often starting with an oxidative reaction involving P450 enzymes. Hence, the… (more)

▼ Drugs and other xenobiotic compounds exhibit different transformations upon entering the human body, most often starting with an oxidative reaction involving P450 enzymes. Hence, the effectiveness and half-life, and even the toxicity of these drugs is determined in part to their metabolism. Thus, it is imperative to produce better models, either experimental or theoretical, to facilitate the understanding and predict the behaviour of these processes. Herein, I present a computational study using hybrid quantum mechanics/molecular mechanics (QM/MM) and density functional theory (DFT) methodologies to model enzymatic metabolism reactions. The work particularly emphasises on the reactivity patterns of the active species of cytochrome P450, i.e. Compound I or the iron(IV)-oxo heme cation radical species, through the use of biomimetic models and enzymatic structures. I initially started the work with a thorough benchmark study on the reproducibility and limitations of DFT methods and compare a set of calculated free energy of activations against experimental reaction rates for a biomimetic FeIVO model. In particular, I focus on a range of density functional theory methods, basis sets, empirical dispersion corrections and solvation as well as entropic effects on the free energy of activation. Based on these studies a recommended set of methods and procedures is proposed. Thereafter, a series of projects explore the reactivity of biomimetic models of Compound I against a number of model substrates. Starting with a model of a carbene ligated iron(IV)-oxo system that shows catalytic properties dramatically altered with respect to P450 CpdI. Through DFT characterization and reactivity with a set of common substrates I establish the electronic and catalytic differences. A subsequent set of projects explore the chemistry of a set of iron(IV)-oxo biomimetic models of Compound I with either a pure computational or a mixed computational-experimental approach. Sound characterizations of the catalytic properties and mechanistic descriptions of such systems are presented often with comparisons to P450-Compound I. A gas phase electron deficient metalloporphyrin model, TPFFP+â€¢ is explored giving comprehensive evidence and rationalization into the distinctions between the mechanisms of aromatic vs aliphatic hydroxylation with common aromatic substrates. Further experiments and modelling were performed in a follow up project where a stable cationic intermediate is formed in contrast to the more common radical intermediate chemistry as seen in CpdI with the same substrate. Following this investigations, a rather more applied set of projects is presented. First the capabilities of a simplified P450 model are explored for the prediction of toxic metabolic products and sites of metabolism (SOMs) derived from P450-oxidations on a common phthalate derived substrate found frequently on cosmetic products and pharmaceutical formulations, revealing reaches and limitations of this approach. Lastly, a comprehensive DFT and QM/MM approach is… Advisors/Committee Members: MUNRO, ANDREW AW, De Visser, Samuel, Munro, Andrew.

Subjects/Keywords: DFT; P450; Computational Chemistry; Drug Metabolism

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Cantu Reinhard, F. G. (2018). A Computational Chemistry Approach to Cytochrome P450 Metabolism. (Doctoral Dissertation). University of Manchester. Retrieved from http://www.manchester.ac.uk/escholar/uk-ac-man-scw:317301

Chicago Manual of Style (16^th Edition):

Cantu Reinhard, Fabian Gilberto. “A Computational Chemistry Approach to Cytochrome P450 Metabolism.” 2018. Doctoral Dissertation, University of Manchester. Accessed January 23, 2021. http://www.manchester.ac.uk/escholar/uk-ac-man-scw:317301.

MLA Handbook (7^th Edition):

Cantu Reinhard, Fabian Gilberto. “A Computational Chemistry Approach to Cytochrome P450 Metabolism.” 2018. Web. 23 Jan 2021.

Vancouver:

Cantu Reinhard FG. A Computational Chemistry Approach to Cytochrome P450 Metabolism. [Internet] [Doctoral dissertation]. University of Manchester; 2018. [cited 2021 Jan 23]. Available from: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:317301.

Council of Science Editors:

Cantu Reinhard FG. A Computational Chemistry Approach to Cytochrome P450 Metabolism. [Doctoral Dissertation]. University of Manchester; 2018. Available from: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:317301

UCLA

13. Van Valkenburgh, Juno. Development of Small-Molecule Modulators of Nucleotide Metabolism Enzymes.

Degree: Chemistry, 2019, UCLA

URL: http://www.escholarship.org/uc/item/6hs572xd

► In chapter 1, strategies toward the asymmetric synthesis of a deoxycytidine kinase (dCK) inhibitor are presented. Small molecule dCK inhibitors are potential cancer therapeutics: in… (more)

▼ In chapter 1, strategies toward the asymmetric synthesis of a deoxycytidine kinase (dCK) inhibitor are presented. Small molecule dCK inhibitors are potential cancer therapeutics: in combination with inhibition of the de novo deoxyribonucleotide triphosphate biosynthetic pathway, they have been shown to be effective against acute lymphoblastic leukemia in animal models. Our group previously identified a series of chiral dCK inhibitors, of which only the R-enantiomer is responsible for kinase inhibition; we thus sought an asymmetric synthesis of these molecules. We pursued a synthetic route in which an SN2 substitution at the chiral center occurs early in the synthesis, to avoid racemization due to a competing SN1 mechanism, which has been observed in a previous asymmetric synthesis from our group. We utilized (–)-ethyl L-lactate as a starting material, as it contains the required chiral carbon skeleton as well as readily-transformable functional groups. Our initial efforts using a Takai-Utimoto olefination as a key step were unsuccessful. Further strategies were hindered by the reactivity of the 4,6-diaminopyrimidine moiety introduced through the early substitution reaction, and ultimately a successful route was not reached.In chapter 2, the development of ⍺-N-heterocyclic carboxaldehyde thiosemicarbazone (HCT) compounds as anti-proliferative agents is described. HCTs have long been known to have anti-cancer properties, due to various mechanisms which generally involve chelation to a redox active metal. One notable HCT which is an iron chelator is Triapine (3-AP), which is the most promising currently-available ribonucleotide reductase inhibitor. Despite currently being in Phase II clinical trials, 3-AP has poor pharmacokinetic properties, so we developed a series of 3-AP analogs which retain the pyridine scaffold of 3-AP but have modifications on the terminal amine of the thiosemicarbazone. None had significantly improved properties over 3-AP, however. HCTs with an isoquinoline scaffold have also previously been developed as ribonucleotide reductase inhibitors but were not pursued clinically due to poor drug-like properties. We synthesized a series of isoquinoline-based HCTs, several of which synergize strongly with physiologically relevant levels of Cu(II) supplementation. The lead compound 2-79 exhibits nanomolar IC90 values in the presence of copper, giving it potential as a cancer therapeutic.

Subjects/Keywords: Chemistry; cancer therapies; drug design; nucleotide metabolism

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APA (6^th Edition):

Van Valkenburgh, J. (2019). Development of Small-Molecule Modulators of Nucleotide Metabolism Enzymes. (Thesis). UCLA. Retrieved from http://www.escholarship.org/uc/item/6hs572xd

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Van Valkenburgh, Juno. “Development of Small-Molecule Modulators of Nucleotide Metabolism Enzymes.” 2019. Thesis, UCLA. Accessed January 23, 2021. http://www.escholarship.org/uc/item/6hs572xd.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Van Valkenburgh, Juno. “Development of Small-Molecule Modulators of Nucleotide Metabolism Enzymes.” 2019. Web. 23 Jan 2021.

Vancouver:

Van Valkenburgh J. Development of Small-Molecule Modulators of Nucleotide Metabolism Enzymes. [Internet] [Thesis]. UCLA; 2019. [cited 2021 Jan 23]. Available from: http://www.escholarship.org/uc/item/6hs572xd.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Van Valkenburgh J. Development of Small-Molecule Modulators of Nucleotide Metabolism Enzymes. [Thesis]. UCLA; 2019. Available from: http://www.escholarship.org/uc/item/6hs572xd

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Ottawa

14. Tayyabi, Ehsen. Gone Fishing: Synthesis and Design of a Superparamagnetic Nanobait for Trapping Reactive Metabolites In Vivo.

Degree: 2018, University of Ottawa

URL: http://hdl.handle.net/10393/37338

► Adverse drug reactions are common causes of medical injuries. Drug-induced hepatotoxicity remains one of the leading causes of emergency room visits, FDA non-approval, and drug… (more)

Subjects/Keywords: Molecular Imaging; Chemical Biology; MRI; Drug Metabolism

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APA (6^th Edition):

Tayyabi, E. (2018). Gone Fishing: Synthesis and Design of a Superparamagnetic Nanobait for Trapping Reactive Metabolites In Vivo. (Thesis). University of Ottawa. Retrieved from http://hdl.handle.net/10393/37338

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Tayyabi, Ehsen. “Gone Fishing: Synthesis and Design of a Superparamagnetic Nanobait for Trapping Reactive Metabolites In Vivo. ” 2018. Thesis, University of Ottawa. Accessed January 23, 2021. http://hdl.handle.net/10393/37338.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Tayyabi, Ehsen. “Gone Fishing: Synthesis and Design of a Superparamagnetic Nanobait for Trapping Reactive Metabolites In Vivo. ” 2018. Web. 23 Jan 2021.

Vancouver:

Tayyabi E. Gone Fishing: Synthesis and Design of a Superparamagnetic Nanobait for Trapping Reactive Metabolites In Vivo. [Internet] [Thesis]. University of Ottawa; 2018. [cited 2021 Jan 23]. Available from: http://hdl.handle.net/10393/37338.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Tayyabi E. Gone Fishing: Synthesis and Design of a Superparamagnetic Nanobait for Trapping Reactive Metabolites In Vivo. [Thesis]. University of Ottawa; 2018. Available from: http://hdl.handle.net/10393/37338

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Adelaide

15. Gourlay, Geoffrey Keith. Pyridine nucleotide involvement in rat hepatic microsomal drug metabolism.

Degree: 1976, University of Adelaide

URL: http://hdl.handle.net/2440/20177

Subjects/Keywords: Drug metabolism.; Coenzymes.

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APA (6^th Edition):

Gourlay, G. K. (1976). Pyridine nucleotide involvement in rat hepatic microsomal drug metabolism. (Thesis). University of Adelaide. Retrieved from http://hdl.handle.net/2440/20177

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Gourlay, Geoffrey Keith. “Pyridine nucleotide involvement in rat hepatic microsomal drug metabolism.” 1976. Thesis, University of Adelaide. Accessed January 23, 2021. http://hdl.handle.net/2440/20177.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Gourlay, Geoffrey Keith. “Pyridine nucleotide involvement in rat hepatic microsomal drug metabolism.” 1976. Web. 23 Jan 2021.

Vancouver:

Gourlay GK. Pyridine nucleotide involvement in rat hepatic microsomal drug metabolism. [Internet] [Thesis]. University of Adelaide; 1976. [cited 2021 Jan 23]. Available from: http://hdl.handle.net/2440/20177.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Gourlay GK. Pyridine nucleotide involvement in rat hepatic microsomal drug metabolism. [Thesis]. University of Adelaide; 1976. Available from: http://hdl.handle.net/2440/20177

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Illinois – Chicago

16. Huang, Ke. In vitro Investigation of Metabolism, Bioactivation, and Botanical-Drug Interactions of Licorice.

Degree: 2017, University of Illinois – Chicago

URL: http://hdl.handle.net/10027/21723

► The dried roots of licorice have been consumed for the past 6000 years as a flavoring and sweetening agent in the western world and in… (more)

▼ The dried roots of licorice have been consumed for the past 6000 years as a flavoring and sweetening agent in the western world and in Asian countries for their anti-allergic and anti-inflammatory agent properties. Among the constituents identified in popular licorice species, few have been studied for metabolism by human cytochrome P450 enzymes. Glabridin in vitro metabolism was studied with respect to metabolic stability, metabolite identification, and identification of metabolizing enzymes. Glabridin was metabolized with low hepatic clearance. In the incubations of glabridin with human liver microsomes and rat liver microsomes, six glabridin metabolites were observed. The D-ring diols formed via unstable epoxides were the major glabridin metabolites, and this finding was confirmed by treating glabridin treated with the epoxide-forming reagent mCPBA. Cytochrome P450 isozyme 1A2, 2C9, and 3A4 were found to be the major enzymes responsible for the formation of the diol metabolites while CYP3A4 and CYP2C9 were predominantly responsible for the other metabolites. A fast triple quadrupole mass spectrometer-based approach was developed that can detect positively and negatively charged GSH conjugates in a single analysis without the need for advance knowledge of the elemental compositions of potential conjugates and while avoiding false positives. This approach utilized UHPLC instead of HPLC to shorten separation time and enhance sensitivity, incorporated stable-isotope labeled GSH to avoid false positives, and used fast polarity switching electrospray MS/MS to detect GSH conjugates that form positive and/or negative ions. The method was used to study the bioactivation of a licorice extract from Glycyrrhiza glabra. The licorice extracts showed significant inhibition of CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP3A4 when the extract concentration was increased from 1 µg/mL to 20 µg/mL. Significant inhibition of CYP2C8, CYP2C9 and CYP2C19 was observed, while CYP2B6 and CYP3A4 were moderately inhibited. CYP2C9 was inhibited the most with IC50 values of 0.6 µg/mL for licorice extract and 2.2 µM for glabridin. As a systematic approach to identify the CYP2C9 and CYP3A4 inhibitors, 13 sub-fractions of the crude licorice extract were tested. Fractions that showed significant inhibition were selected for further compound isolation and characterization. Diligent database searching and dereplication of known licorice compounds were used to determine possible chemical structures of the most potent inhibitors of CYP2C9 and CYP3A4. Due to lack of standards for these licorice compounds, the proposed chemical structures could not be identified at this time. Advisors/Committee Members: van Breemen, Richard B (advisor), Burdette, Joanna E (committee member), Che, Chun-Tao (committee member), Waller, Donald P (committee member), Nikolic, Dejan S (committee member), van Breemen, Richard B (chair).

Subjects/Keywords: Licorice; Glabridin; Metabolism; Metabolic Activation; Drug Inhibition

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Huang, K. (2017). In vitro Investigation of Metabolism, Bioactivation, and Botanical-Drug Interactions of Licorice. (Thesis). University of Illinois – Chicago. Retrieved from http://hdl.handle.net/10027/21723

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Huang, Ke. “In vitro Investigation of Metabolism, Bioactivation, and Botanical-Drug Interactions of Licorice.” 2017. Thesis, University of Illinois – Chicago. Accessed January 23, 2021. http://hdl.handle.net/10027/21723.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Huang, Ke. “In vitro Investigation of Metabolism, Bioactivation, and Botanical-Drug Interactions of Licorice.” 2017. Web. 23 Jan 2021.

Vancouver:

Huang K. In vitro Investigation of Metabolism, Bioactivation, and Botanical-Drug Interactions of Licorice. [Internet] [Thesis]. University of Illinois – Chicago; 2017. [cited 2021 Jan 23]. Available from: http://hdl.handle.net/10027/21723.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Huang K. In vitro Investigation of Metabolism, Bioactivation, and Botanical-Drug Interactions of Licorice. [Thesis]. University of Illinois – Chicago; 2017. Available from: http://hdl.handle.net/10027/21723

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Manchester

17. Wood, Francesca. Optimisation of in vitro methodology for drug metabolism studies to improve prediction of hepatic drug clearance.

Degree: PhD, 2016, University of Manchester

URL: https://www.research.manchester.ac.uk/portal/en/theses/optimisation-of-in-vitro-methodology-for-drug-metabolism-studies-to-improve-prediction-of-hepatic-drug-clearance(0786531a-2e10-48a7-9b35-e2e7e1935338).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.764443

► As a critical parameter in pharmacokinetics, prediction of clearance is an integral aspect of drug discovery programmes. Since the liver is the major site of… (more)

▼ As a critical parameter in pharmacokinetics, prediction of clearance is an integral aspect of drug discovery programmes. Since the liver is the major site of xenobiotic biotransformation, accurate prediction of hepatic clearance (CLh) is vital. The use of cellular and subcellular in vitro systems for this purpose is common practice; however, prediction accuracy tends to be poor. The aim of this thesis was to explore potential contributing factors to the underprediction of in vivo clearance, specifically with relation to the in vitro methodology of hepatocyte clearance assays, which is largely unstandardised. Literature data analyses highlighted an overall clearance-dependent trend of underprediction in both human and rat hepatocytes, indicating a fundamental in vitro system bias which is independent of species. During initial investigation of incubation conditions, the format of hepatocyte assays (suspension in microcentrifuge tubes, 96-well plates, 24-well plates and short-term monolayer culture) was demonstrated to influence determined intrinsic clearance (CLint). Differences in midazolam CLint were observed not only between suspended and short-term cultured hepatocytes, but also between suspended hepatocytes in different vessels/plate formats. The applicability of 1 µM as a generic substrate incubation concentration for determination of CLint by substrate depletion was evaluated in rat hepatocytes using nine well-characterised drugs. For seven of the nine drugs, a statistically significantly (p < 0.05) higher CLint was observed in determinations of 0.1 µM substrate as opposed to 1 µM, highlighting the potential for false determinations using current practices. Cofactor depletion in isolated hepatocytes was investigated based on previous speculation as the cause of clearance-dependent underprediction of in vivo clearance. Although moderate increases in CLint were observed with the addition of NADPH to hepatocyte incubations, this was subsequently attributed to the replenishment of NADPH in membrane-damaged hepatocytes. Retained functionality of metabolic enzymes in cells which would generally be considered non-viable by trypan blue exclusion was indicated in comparisons of unpurified and Percoll-purified cryopreserved hepatocytes. This phenomenon was conclusively demonstrated in incubations of permeabilised hepatocytes supplemented with NADPH, revealing a need for re-evaluation of the use of plasma membrane integrity (trypan blue exclusion) as a measure of viability in metabolic studies. ATP content was considered as a potential alternative measure; however no significant correlations were found between ATP content, trypan blue exclusion and the CLint of nine drugs in associated preparations. The effect of shaking on CLint in rat hepatocytes was also examined. For 10 out of 12 drugs, CLint determined at 900 rpm was significantly (p < 0.05) higher than in static incubations. Three potential mechanisms were hypothesised: plasma membrane damage, increased substrate distribution throughout the bulk medium and reduction…

Subjects/Keywords: 610; drug metabolism; hepatocytes; hepatic clearance

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Wood, F. (2016). Optimisation of in vitro methodology for drug metabolism studies to improve prediction of hepatic drug clearance. (Doctoral Dissertation). University of Manchester. Retrieved from https://www.research.manchester.ac.uk/portal/en/theses/optimisation-of-in-vitro-methodology-for-drug-metabolism-studies-to-improve-prediction-of-hepatic-drug-clearance(0786531a-2e10-48a7-9b35-e2e7e1935338).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.764443

Chicago Manual of Style (16^th Edition):

Wood, Francesca. “Optimisation of in vitro methodology for drug metabolism studies to improve prediction of hepatic drug clearance.” 2016. Doctoral Dissertation, University of Manchester. Accessed January 23, 2021. https://www.research.manchester.ac.uk/portal/en/theses/optimisation-of-in-vitro-methodology-for-drug-metabolism-studies-to-improve-prediction-of-hepatic-drug-clearance(0786531a-2e10-48a7-9b35-e2e7e1935338).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.764443.

MLA Handbook (7^th Edition):

Wood, Francesca. “Optimisation of in vitro methodology for drug metabolism studies to improve prediction of hepatic drug clearance.” 2016. Web. 23 Jan 2021.

Vancouver:

Wood F. Optimisation of in vitro methodology for drug metabolism studies to improve prediction of hepatic drug clearance. [Internet] [Doctoral dissertation]. University of Manchester; 2016. [cited 2021 Jan 23]. Available from: https://www.research.manchester.ac.uk/portal/en/theses/optimisation-of-in-vitro-methodology-for-drug-metabolism-studies-to-improve-prediction-of-hepatic-drug-clearance(0786531a-2e10-48a7-9b35-e2e7e1935338).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.764443.

Council of Science Editors:

Wood F. Optimisation of in vitro methodology for drug metabolism studies to improve prediction of hepatic drug clearance. [Doctoral Dissertation]. University of Manchester; 2016. Available from: https://www.research.manchester.ac.uk/portal/en/theses/optimisation-of-in-vitro-methodology-for-drug-metabolism-studies-to-improve-prediction-of-hepatic-drug-clearance(0786531a-2e10-48a7-9b35-e2e7e1935338).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.764443

University of Bath

18. Makwana, Amit. Studies on the N-dealkylation of codeine by Candida tropicalis.

Degree: PhD, 1990, University of Bath

URL: https://researchportal.bath.ac.uk/en/studentthesis/studies-on-the-ndealkylation-of-codeine-by-candida-tropicalis(fbd61dc3-4cc3-4dc5-b10d-9fdc70a5aeae).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.278237

Subjects/Keywords: 615.1; Drug metabolism

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APA (6^th Edition):

Makwana, A. (1990). Studies on the N-dealkylation of codeine by Candida tropicalis. (Doctoral Dissertation). University of Bath. Retrieved from https://researchportal.bath.ac.uk/en/studentthesis/studies-on-the-ndealkylation-of-codeine-by-candida-tropicalis(fbd61dc3-4cc3-4dc5-b10d-9fdc70a5aeae).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.278237

Chicago Manual of Style (16^th Edition):

Makwana, Amit. “Studies on the N-dealkylation of codeine by Candida tropicalis.” 1990. Doctoral Dissertation, University of Bath. Accessed January 23, 2021. https://researchportal.bath.ac.uk/en/studentthesis/studies-on-the-ndealkylation-of-codeine-by-candida-tropicalis(fbd61dc3-4cc3-4dc5-b10d-9fdc70a5aeae).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.278237.

MLA Handbook (7^th Edition):

Makwana, Amit. “Studies on the N-dealkylation of codeine by Candida tropicalis.” 1990. Web. 23 Jan 2021.

Vancouver:

Makwana A. Studies on the N-dealkylation of codeine by Candida tropicalis. [Internet] [Doctoral dissertation]. University of Bath; 1990. [cited 2021 Jan 23]. Available from: https://researchportal.bath.ac.uk/en/studentthesis/studies-on-the-ndealkylation-of-codeine-by-candida-tropicalis(fbd61dc3-4cc3-4dc5-b10d-9fdc70a5aeae).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.278237.

Council of Science Editors:

Makwana A. Studies on the N-dealkylation of codeine by Candida tropicalis. [Doctoral Dissertation]. University of Bath; 1990. Available from: https://researchportal.bath.ac.uk/en/studentthesis/studies-on-the-ndealkylation-of-codeine-by-candida-tropicalis(fbd61dc3-4cc3-4dc5-b10d-9fdc70a5aeae).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.278237

University of the Western Cape

19. Ntshongontshi, Nomaphelo. Cytochrome P450-3A4/copper-poly(propylene imine)- polypyrrole star co-polymer Nanobiosensor system for delavirdine – a non-nucleoside reverse transcriptase inhibitor HIV drug .

Degree: 2014, University of the Western Cape

URL: http://hdl.handle.net/11394/4446

► HIV and AIDS are among the world's pandemics that pose serious concern to almost every individual in the world. With the current level of availability… (more)

▼ HIV and AIDS are among the world's pandemics that pose serious concern to almost every individual in the world. With the current level of availability of anti-retroviral (ARV) drugs and the ease of accessibility of treatment in many countries such as South Africa, the disease can be controlled by suppressing the viral load of an infected individual. These anti HIV drugs such as delavirdine are metabolised by enzymes which are found in the liver microsomes, particularly those of the cytochrome P450 family. Due to the fact that the metabolic rate of a patient determines the effect of the drug, the drug could either have a beneficial or an adverse effect once it is administered. It is therefore imperative that the metabolic profile of a patient is determined at point-of-care is necessary for proper dosing of the ARV drugs. In this project a nanobiosensor system was devised and used for the determination of the metabolism of delavirdine, a non-nucleoside reverse transcriptase inhibitor (NNRTI) ARV drug. The nanobiosensor was prepared by the entrapment of the isoenzyme CYP3A4 into a pre-formed electro active carrier matrice consisting of a dendrimeric copper generation-2 poly (propylene imine)-co-polypyrrole star copolymer (Cu(G2PPI)-co-PPy). The metallo-dendrimer was used as a host for the enzyme and provided thenecessary bio-compatible environment that allowed the direct transfer of electrons between the enzyme's active centres and platinum electrode surface. Copper was the choice of metal used in the study due to its properties. Copper is a malleable, ductile and a good conductor of both heat and electricity. It is a better conductor than most metals. Silver which also belongs to group 1b in the periodic table is a better electrical conductor than copper but copper has better corrosion resistance and is a more abundant and hence it is a cheaper material to use. Cu(G2PPI)-co-PPy was prepared by the incorporation of the copper metal into the G2PPI and the electropolymerization of pyrrole onto the Cu(G2PPI). The incorporation of Cu into G2PPI was determined by FTIR which did not show the presence of the Cu but showed an increase in the intensities of the peaks after the incorporation. The surface morphology of Cu (G2PPI) was confirmed by the use of HRSEM which showed a difference in the surface morphology of the dendrimer moiety with the addition of the copper metal. The HRSEM images after Cu incorporation resulted in the change from rough surface to smooth surface with open cavities which were essential for the entrapment of the biological systems (CYP3A4). Energy dispersive spectrometry (EDS) and HRTEM were used to confirm the presence of spherically shaped copper nanoparticles in the Cu (G2PPI) and were found to have a size distribution of 12-17 nm with an average particle size of 15nm. The star copolymer (Cu(G2PPI)-co-PPy) was characterised using cyclic voltammetrywhere it was confirmed that the material was electroactive and conducting due to electron movement along the polymer chain. A diffusion co-efficient (D₀)… Advisors/Committee Members: Iwuoha, Emmanuel I (advisor).

Subjects/Keywords: Biosensor; Delavirdine drug; Metabolism; Cyclic voltammetry (CV)

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APA (6^th Edition):

Ntshongontshi, N. (2014). Cytochrome P450-3A4/copper-poly(propylene imine)- polypyrrole star co-polymer Nanobiosensor system for delavirdine – a non-nucleoside reverse transcriptase inhibitor HIV drug . (Thesis). University of the Western Cape. Retrieved from http://hdl.handle.net/11394/4446

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Ntshongontshi, Nomaphelo. “Cytochrome P450-3A4/copper-poly(propylene imine)- polypyrrole star co-polymer Nanobiosensor system for delavirdine – a non-nucleoside reverse transcriptase inhibitor HIV drug .” 2014. Thesis, University of the Western Cape. Accessed January 23, 2021. http://hdl.handle.net/11394/4446.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Ntshongontshi, Nomaphelo. “Cytochrome P450-3A4/copper-poly(propylene imine)- polypyrrole star co-polymer Nanobiosensor system for delavirdine – a non-nucleoside reverse transcriptase inhibitor HIV drug .” 2014. Web. 23 Jan 2021.

Vancouver:

Ntshongontshi N. Cytochrome P450-3A4/copper-poly(propylene imine)- polypyrrole star co-polymer Nanobiosensor system for delavirdine – a non-nucleoside reverse transcriptase inhibitor HIV drug . [Internet] [Thesis]. University of the Western Cape; 2014. [cited 2021 Jan 23]. Available from: http://hdl.handle.net/11394/4446.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Ntshongontshi N. Cytochrome P450-3A4/copper-poly(propylene imine)- polypyrrole star co-polymer Nanobiosensor system for delavirdine – a non-nucleoside reverse transcriptase inhibitor HIV drug . [Thesis]. University of the Western Cape; 2014. Available from: http://hdl.handle.net/11394/4446

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Washington University in St. Louis

20. Guggisberg, Ann Marie. Discovery and characterization of a novel class of metabolic regulators in the malaria parasite Plasmodium falciparum.

Degree: PhD, Biology & Biomedical Sciences (Molecular Genetics & Genomics), 2016, Washington University in St. Louis

URL: https://openscholarship.wustl.edu/art_sci_etds/989

► The malaria parasite, Plasmodium falciparum, infects hundreds of millions of people per year and causes hundreds of thousands of deaths. Within the host red blood… (more)

Subjects/Keywords: drug resistance, malaria, metabolism, parasitology; Biology

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Guggisberg, A. M. (2016). Discovery and characterization of a novel class of metabolic regulators in the malaria parasite Plasmodium falciparum. (Doctoral Dissertation). Washington University in St. Louis. Retrieved from https://openscholarship.wustl.edu/art_sci_etds/989

Chicago Manual of Style (16^th Edition):

Guggisberg, Ann Marie. “Discovery and characterization of a novel class of metabolic regulators in the malaria parasite Plasmodium falciparum.” 2016. Doctoral Dissertation, Washington University in St. Louis. Accessed January 23, 2021. https://openscholarship.wustl.edu/art_sci_etds/989.

MLA Handbook (7^th Edition):

Guggisberg, Ann Marie. “Discovery and characterization of a novel class of metabolic regulators in the malaria parasite Plasmodium falciparum.” 2016. Web. 23 Jan 2021.

Vancouver:

Guggisberg AM. Discovery and characterization of a novel class of metabolic regulators in the malaria parasite Plasmodium falciparum. [Internet] [Doctoral dissertation]. Washington University in St. Louis; 2016. [cited 2021 Jan 23]. Available from: https://openscholarship.wustl.edu/art_sci_etds/989.

Council of Science Editors:

Guggisberg AM. Discovery and characterization of a novel class of metabolic regulators in the malaria parasite Plasmodium falciparum. [Doctoral Dissertation]. Washington University in St. Louis; 2016. Available from: https://openscholarship.wustl.edu/art_sci_etds/989

21. Berg, Aad. Cytochrome P-450-Substrate Interaction and Hepatic Drug Metabolism in the Mouse.

Degree: Department of Radiation Oncology, 1977, Erasmus University Medical Center

URL: http://hdl.handle.net/1765/26191

► textabstractA drug which has entered the circulation, may be eliminated as such by the kidney and excreted in the urine. This depends on the lipid-solubility… (more)

Subjects/Keywords: drug metabolism; mouse

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APA (6^th Edition):

Berg, A. (1977). Cytochrome P-450-Substrate Interaction and Hepatic Drug Metabolism in the Mouse. (Doctoral Dissertation). Erasmus University Medical Center. Retrieved from http://hdl.handle.net/1765/26191

Chicago Manual of Style (16^th Edition):

Berg, Aad. “Cytochrome P-450-Substrate Interaction and Hepatic Drug Metabolism in the Mouse.” 1977. Doctoral Dissertation, Erasmus University Medical Center. Accessed January 23, 2021. http://hdl.handle.net/1765/26191.

MLA Handbook (7^th Edition):

Berg, Aad. “Cytochrome P-450-Substrate Interaction and Hepatic Drug Metabolism in the Mouse.” 1977. Web. 23 Jan 2021.

Vancouver:

Berg A. Cytochrome P-450-Substrate Interaction and Hepatic Drug Metabolism in the Mouse. [Internet] [Doctoral dissertation]. Erasmus University Medical Center; 1977. [cited 2021 Jan 23]. Available from: http://hdl.handle.net/1765/26191.

Council of Science Editors:

Berg A. Cytochrome P-450-Substrate Interaction and Hepatic Drug Metabolism in the Mouse. [Doctoral Dissertation]. Erasmus University Medical Center; 1977. Available from: http://hdl.handle.net/1765/26191

University of Bath

22. Fordyce, Karen. Aspects of genetic and environmental control of phase II metabolism.

Degree: PhD, 1987, University of Bath

URL: https://researchportal.bath.ac.uk/en/studentthesis/aspects-of-genetic-and-environmental-control-of-phase-ii-metabolism(06cc680c-9bad-407e-b21c-9817681f55ed).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.375338

Subjects/Keywords: 615.1; Drug metabolism

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APA (6^th Edition):

Fordyce, K. (1987). Aspects of genetic and environmental control of phase II metabolism. (Doctoral Dissertation). University of Bath. Retrieved from https://researchportal.bath.ac.uk/en/studentthesis/aspects-of-genetic-and-environmental-control-of-phase-ii-metabolism(06cc680c-9bad-407e-b21c-9817681f55ed).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.375338

Chicago Manual of Style (16^th Edition):

Fordyce, Karen. “Aspects of genetic and environmental control of phase II metabolism.” 1987. Doctoral Dissertation, University of Bath. Accessed January 23, 2021. https://researchportal.bath.ac.uk/en/studentthesis/aspects-of-genetic-and-environmental-control-of-phase-ii-metabolism(06cc680c-9bad-407e-b21c-9817681f55ed).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.375338.

MLA Handbook (7^th Edition):

Fordyce, Karen. “Aspects of genetic and environmental control of phase II metabolism.” 1987. Web. 23 Jan 2021.

Vancouver:

Fordyce K. Aspects of genetic and environmental control of phase II metabolism. [Internet] [Doctoral dissertation]. University of Bath; 1987. [cited 2021 Jan 23]. Available from: https://researchportal.bath.ac.uk/en/studentthesis/aspects-of-genetic-and-environmental-control-of-phase-ii-metabolism(06cc680c-9bad-407e-b21c-9817681f55ed).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.375338.

Council of Science Editors:

Fordyce K. Aspects of genetic and environmental control of phase II metabolism. [Doctoral Dissertation]. University of Bath; 1987. Available from: https://researchportal.bath.ac.uk/en/studentthesis/aspects-of-genetic-and-environmental-control-of-phase-ii-metabolism(06cc680c-9bad-407e-b21c-9817681f55ed).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.375338

University of Manchester

23. Cantu Guerra, Fabian. A computational chemistry approach to cytochrome P450 metabolism.

Degree: PhD, 2018, University of Manchester

URL: https://www.research.manchester.ac.uk/portal/en/theses/a-computational-chemistry-approach-to-cytochrome-p450-metabolism(e42a5d4b-ead5-4687-950e-5f63d6093f1e).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.799271

► Drugs and other xenobiotic compounds exhibit different transformations upon entering the human body, most often starting with an oxidative reaction involving P450 enzymes. Hence, the… (more)

▼ Drugs and other xenobiotic compounds exhibit different transformations upon entering the human body, most often starting with an oxidative reaction involving P450 enzymes. Hence, the effectiveness and half-life, and even the toxicity of these drugs is determined in part to their metabolism. Thus, it is imperative to produce better models, either experimental or theoretical, to facilitate the understanding and predict the behaviour of these processes. Herein, I present a computational study using hybrid quantum mechanics/molecular mechanics (QM/MM) and density functional theory (DFT) methodologies to model enzymatic metabolism reactions. The work particularly emphasises on the reactivity patterns of the active species of cytochrome P450, i.e. Compound I or the iron(IV)-oxo heme cation radical species, through the use of biomimetic models and enzymatic structures. I initially started the work with a thorough benchmark study on the reproducibility and limitations of DFT methods and compare a set of calculated free energy of activations against experimental reaction rates for a biomimetic FeIVO model. In particular, I focus on a range of density functional theory methods, basis sets, empirical dispersion corrections and solvation as well as entropic effects on the free energy of activation. Based on these studies a recommended set of methods and procedures is proposed. Thereafter, a series of projects explore the reactivity of biomimetic models of Compound I against a number of model substrates. Starting with a model of a carbene ligated iron(IV)-oxo system that shows catalytic properties dramatically altered with respect to P450 CpdI. Through DFT characterization and reactivity with a set of common substrates I establish the electronic and catalytic differences. A subsequent set of projects explore the chemistry of a set of iron(IV)-oxo biomimetic models of Compound I with either a pure computational or a mixed computational-experimental approach. Sound characterizations of the catalytic properties and mechanistic descriptions of such systems are presented often with comparisons to P450-Compound I. A gas phase electron deficient metalloporphyrin model, TPFFP+â¢ is explored giving comprehensive evidence and rationalization into the distinctions between the mechanisms of aromatic vs aliphatic hydroxylation with common aromatic substrates. Further experiments and modelling were performed in a follow up project where a stable cationic intermediate is formed in contrast to the more common radical intermediate chemistry as seen in CpdI with the same substrate. Following this investigations, a rather more applied set of projects is presented. First the capabilities of a simplified P450 model are explored for the prediction of toxic metabolic products and sites of metabolism (SOMs) derived from P450-oxidations on a common phthalate derived substrate found frequently on cosmetic products and pharmaceutical formulations, revealing reaches and limitations of this approach. Lastly, a comprehensive DFT and QM/MM approach is…

Subjects/Keywords: DFT; P450; Computational Chemistry; Drug Metabolism

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APA (6^th Edition):

Cantu Guerra, F. (2018). A computational chemistry approach to cytochrome P450 metabolism. (Doctoral Dissertation). University of Manchester. Retrieved from https://www.research.manchester.ac.uk/portal/en/theses/a-computational-chemistry-approach-to-cytochrome-p450-metabolism(e42a5d4b-ead5-4687-950e-5f63d6093f1e).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.799271

Chicago Manual of Style (16^th Edition):

Cantu Guerra, Fabian. “A computational chemistry approach to cytochrome P450 metabolism.” 2018. Doctoral Dissertation, University of Manchester. Accessed January 23, 2021. https://www.research.manchester.ac.uk/portal/en/theses/a-computational-chemistry-approach-to-cytochrome-p450-metabolism(e42a5d4b-ead5-4687-950e-5f63d6093f1e).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.799271.

MLA Handbook (7^th Edition):

Cantu Guerra, Fabian. “A computational chemistry approach to cytochrome P450 metabolism.” 2018. Web. 23 Jan 2021.

Vancouver:

Cantu Guerra F. A computational chemistry approach to cytochrome P450 metabolism. [Internet] [Doctoral dissertation]. University of Manchester; 2018. [cited 2021 Jan 23]. Available from: https://www.research.manchester.ac.uk/portal/en/theses/a-computational-chemistry-approach-to-cytochrome-p450-metabolism(e42a5d4b-ead5-4687-950e-5f63d6093f1e).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.799271.

Council of Science Editors:

Cantu Guerra F. A computational chemistry approach to cytochrome P450 metabolism. [Doctoral Dissertation]. University of Manchester; 2018. Available from: https://www.research.manchester.ac.uk/portal/en/theses/a-computational-chemistry-approach-to-cytochrome-p450-metabolism(e42a5d4b-ead5-4687-950e-5f63d6093f1e).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.799271

University of Sydney

24. Painter, Arran Blake. Altered drug metabolism and clearance pathways in cancer cachexia .

Degree: 2014, University of Sydney

URL: http://hdl.handle.net/2123/12269

► Cancer cachexia, a syndrome of lean and adipose tissue loss in cancer patients, is associated with reduced quality of life, poor survival outcomes and increased… (more)

Subjects/Keywords: Cancer; cachexia; inflammation; drug metabolism; transport

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APA (6^th Edition):

Painter, A. B. (2014). Altered drug metabolism and clearance pathways in cancer cachexia . (Thesis). University of Sydney. Retrieved from http://hdl.handle.net/2123/12269

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Painter, Arran Blake. “Altered drug metabolism and clearance pathways in cancer cachexia .” 2014. Thesis, University of Sydney. Accessed January 23, 2021. http://hdl.handle.net/2123/12269.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Painter, Arran Blake. “Altered drug metabolism and clearance pathways in cancer cachexia .” 2014. Web. 23 Jan 2021.

Vancouver:

Painter AB. Altered drug metabolism and clearance pathways in cancer cachexia . [Internet] [Thesis]. University of Sydney; 2014. [cited 2021 Jan 23]. Available from: http://hdl.handle.net/2123/12269.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Painter AB. Altered drug metabolism and clearance pathways in cancer cachexia . [Thesis]. University of Sydney; 2014. Available from: http://hdl.handle.net/2123/12269

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Vanderbilt University

25. Crouch, Rachel Denise. Aldehyde Oxidase Drug Metabolism: Evaluation of Drug Interaction Potential and Allometric Scaling Methods to Predict Human Pharmacokinetics.

Degree: PhD, Pharmacology, 2016, Vanderbilt University

URL: http://hdl.handle.net/1803/14636

► Unacceptable pharmacokinetics (PK) relating to aldehyde oxidase (AO) metabolism have resulted in clinical failure of several promising drug candidates, yet reliable and standardized methods to… (more)

Subjects/Keywords: aldehyde oxidase; allometric scaling; drug metabolism; pharmacokinetics; drug interaction

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APA (6^th Edition):

Crouch, R. D. (2016). Aldehyde Oxidase Drug Metabolism: Evaluation of Drug Interaction Potential and Allometric Scaling Methods to Predict Human Pharmacokinetics. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/14636

Chicago Manual of Style (16^th Edition):

Crouch, Rachel Denise. “Aldehyde Oxidase Drug Metabolism: Evaluation of Drug Interaction Potential and Allometric Scaling Methods to Predict Human Pharmacokinetics.” 2016. Doctoral Dissertation, Vanderbilt University. Accessed January 23, 2021. http://hdl.handle.net/1803/14636.

MLA Handbook (7^th Edition):

Crouch, Rachel Denise. “Aldehyde Oxidase Drug Metabolism: Evaluation of Drug Interaction Potential and Allometric Scaling Methods to Predict Human Pharmacokinetics.” 2016. Web. 23 Jan 2021.

Vancouver:

Crouch RD. Aldehyde Oxidase Drug Metabolism: Evaluation of Drug Interaction Potential and Allometric Scaling Methods to Predict Human Pharmacokinetics. [Internet] [Doctoral dissertation]. Vanderbilt University; 2016. [cited 2021 Jan 23]. Available from: http://hdl.handle.net/1803/14636.

Council of Science Editors:

Crouch RD. Aldehyde Oxidase Drug Metabolism: Evaluation of Drug Interaction Potential and Allometric Scaling Methods to Predict Human Pharmacokinetics. [Doctoral Dissertation]. Vanderbilt University; 2016. Available from: http://hdl.handle.net/1803/14636

University of Toronto

26. Huang, Yiying. Characterizing the Expression and Localization of Drug Transporters and Metabolic Enzymes in the testes of Uninfected and HIV-1 Infected, Treated Subjects – Potential Contribution to an HIV-1 Sanctuary.

Degree: 2015, University of Toronto

URL: http://hdl.handle.net/1807/70405

►

Previous studies have reported that HIV-1 is capable of both acute and persistent infection in the testes. The naturally restrictive environment in the testes, due… (more)

Subjects/Keywords: Drug Metabolism; Drug Transporters; HIV; Sanctuary Site; Testes; 0572

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APA (6^th Edition):

Huang, Y. (2015). Characterizing the Expression and Localization of Drug Transporters and Metabolic Enzymes in the testes of Uninfected and HIV-1 Infected, Treated Subjects – Potential Contribution to an HIV-1 Sanctuary. (Masters Thesis). University of Toronto. Retrieved from http://hdl.handle.net/1807/70405

Chicago Manual of Style (16^th Edition):

Huang, Yiying. “Characterizing the Expression and Localization of Drug Transporters and Metabolic Enzymes in the testes of Uninfected and HIV-1 Infected, Treated Subjects – Potential Contribution to an HIV-1 Sanctuary.” 2015. Masters Thesis, University of Toronto. Accessed January 23, 2021. http://hdl.handle.net/1807/70405.

MLA Handbook (7^th Edition):

Huang, Yiying. “Characterizing the Expression and Localization of Drug Transporters and Metabolic Enzymes in the testes of Uninfected and HIV-1 Infected, Treated Subjects – Potential Contribution to an HIV-1 Sanctuary.” 2015. Web. 23 Jan 2021.

Vancouver:

Huang Y. Characterizing the Expression and Localization of Drug Transporters and Metabolic Enzymes in the testes of Uninfected and HIV-1 Infected, Treated Subjects – Potential Contribution to an HIV-1 Sanctuary. [Internet] [Masters thesis]. University of Toronto; 2015. [cited 2021 Jan 23]. Available from: http://hdl.handle.net/1807/70405.

Council of Science Editors:

Huang Y. Characterizing the Expression and Localization of Drug Transporters and Metabolic Enzymes in the testes of Uninfected and HIV-1 Infected, Treated Subjects – Potential Contribution to an HIV-1 Sanctuary. [Masters Thesis]. University of Toronto; 2015. Available from: http://hdl.handle.net/1807/70405

Universiteit Utrecht

27. Waterschoot, R.A.B. van. Interplay between CYP3A and drug transporters.

Degree: 2009, Universiteit Utrecht

URL: http://dspace.library.uu.nl:8080/handle/1874/35859

► Cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp/MDR1) are two important detoxifying systems that protect us against many potentially harmful xenobiotics but their activity also strongly… (more)

▼ Cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp/MDR1) are two important detoxifying systems that protect us against many potentially harmful xenobiotics but their activity also strongly limits the absorption of a wide variety of drugs. Both CYP3A and P-gp have a very broad substrate spectrum and it is noteworthy that there is a large overlap between their substrates. In view of this, it has been hypothesized that it is the combined (intestinal) activity of CYP3A and P-gp that makes for efficient first-pass metabolism of many orally administered drugs. P-gp may reduce the probability of CYP3A4 saturation and would also give the enzyme repeated access to its substrates. However, little in vivo evidence for functional synergy between CYP3A and P-gp is currently available. By generating and utilizing novel mouse models we aimed to obtain more insight into the importance of intestinal CYP3A-dependent metabolism and the functional interplay between CYP3A and P-gp. The studies described in this thesis demonstrate the value of knockout and transgenic mouse models to investigate the individual and combined impact of CYP3A and drug transporters such as P-gp on the pharmacokinetics of drugs. For example, the importance of intestinal metabolism has long been a matter of debate but our studies with tissue-specific CYP3A4 transgenic mice have provided unequivocal evidence that the impact of intestinal CYP3A4-dependent metabolism can even surpass that of hepatic metabolism after oral drug administration. The generation of Cyp3a/P-gp-/- mice has provided a novel in vivo tool to get more insight into how CYP3A and P-gp may work together. We demonstrated that the combined absence of both CYP3A and P-gp can result in a dramatic, disproportionate increase in drug exposure with a concomitantly increased (and possibly qualitatively altered) risk of toxicity. Especially with drugs that have a narrow therapeutic window, there are serious risks when such drugs are deliberately or unintentionally co-administered with other drugs or food constituents that interfere with CYP3A and P-gp activity. The risk of such drug-drug and drug-food interactions is especially relevant given the high number and large overlap in substrates and inhibitors for CYP3A and P-gp. Variable activity of CYP3A alone can lead to lethal overdosing or subtherapeutic underdosing of orally taken drugs. It is clear from the work in this thesis that interfering with both CYP3A and P-gp activity could drastically exacerbate such consequences, and should therefore be considered with caution during further drug development and application. Advisors/Committee Members: Beijnen, J.H., Schinkel, A.H..

Subjects/Keywords: Farmacie; Intestinal and hepatic drug metabolism; drug transport; drug toxicity; pharmacokinetics CYP3A; P-glycoprotein; MRP2

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Waterschoot, R. A. B. v. (2009). Interplay between CYP3A and drug transporters. (Doctoral Dissertation). Universiteit Utrecht. Retrieved from http://dspace.library.uu.nl:8080/handle/1874/35859

Chicago Manual of Style (16^th Edition):

Waterschoot, R A B van. “Interplay between CYP3A and drug transporters.” 2009. Doctoral Dissertation, Universiteit Utrecht. Accessed January 23, 2021. http://dspace.library.uu.nl:8080/handle/1874/35859.

MLA Handbook (7^th Edition):

Waterschoot, R A B van. “Interplay between CYP3A and drug transporters.” 2009. Web. 23 Jan 2021.

Vancouver:

Waterschoot RABv. Interplay between CYP3A and drug transporters. [Internet] [Doctoral dissertation]. Universiteit Utrecht; 2009. [cited 2021 Jan 23]. Available from: http://dspace.library.uu.nl:8080/handle/1874/35859.

Council of Science Editors:

Waterschoot RABv. Interplay between CYP3A and drug transporters. [Doctoral Dissertation]. Universiteit Utrecht; 2009. Available from: http://dspace.library.uu.nl:8080/handle/1874/35859

University of California – San Francisco

28. Hosey, Chelsea Mariah. Predicting Drug Disposition by Integrating In Vitro and In Silico Methodology.

Degree: Pharmaceutical Sciences and Pharmacogenomics, 2016, University of California – San Francisco

URL: http://www.escholarship.org/uc/item/5ds3q196

► The safety and efficacy of drugs depend upon appropriate dosing of drugs made possible by understanding the dispositional profile a drug will follow. A drug’s… (more)

▼ The safety and efficacy of drugs depend upon appropriate dosing of drugs made possible by understanding the dispositional profile a drug will follow. A drug’s disposition includes its absorption from an administration site, its distribution throughout the body, and its elimination from the body, characterized by metabolism and excretion. Disposition is often mediated by drug metabolizing enzymes and drug transporters. Alterations in the expression or activity of metabolizing enzymes and transporters can therefore affect the safety or efficacy of a drug and it is necessary to characterize their impact on every drug. The Biopharmaceutics Drug Disposition Classification System (BDDCS) uses the extent of metabolism and solubility of drugs to predict drug disposition, including when transporters and metabolizing enzymes are clinically relevant. Here, we utilized observations from this system to predict the three major routes of drug elimination (metabolism, renal excretion of unchanged drug, and biliary excretion of unchanged drug). These predictions were made by integrating in vitro measurements of permeability rate to predict the extent of metabolism with an in silico logistic regression model we developed that uses calculated polarizability and predicted metabolic stability to predict when poorly metabolized compounds will be eliminated in the urine or the bile. This approach correctly identified 72 ± 9%, 85 ± 2%, and 73 ± 2% of extensively metabolized, biliarily eliminated, and renally eliminated drugs, respectively. We discuss the physiological context through which permeability, polarizability, and metabolic stability may inform the major elimination route. We further developed a model predicting BDDCS class using commercially available in silico models of permeability rate to predict the extent of metabolism and dose number to predict the solubility class. This approach correctly identified 54.1%, 57.8%, 69.3%, and 45.2% of class 1, 2, 3, and 4 drugs, respectively, while in vitro approaches predict with greater accuracy. We correct previously misclassified drugs, discuss reasons for misclassification, incorporate more than 175 additional drugs into the system, and discuss how BDDCS can self-correct when observed and predicted dispositional effects are not aligned. We conclude by reflecting on the demonstrated and potential applications of BDDCS and the importance of predicting drug disposition.

Subjects/Keywords: Pharmaceutical sciences; Biliary Elimination; Biopharmaceutics Drug Disposition Classification System; Drug Disposition; Drug Elimination; Metabolism; Transporters

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APA (6^th Edition):

Hosey, C. M. (2016). Predicting Drug Disposition by Integrating In Vitro and In Silico Methodology. (Thesis). University of California – San Francisco. Retrieved from http://www.escholarship.org/uc/item/5ds3q196

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Hosey, Chelsea Mariah. “Predicting Drug Disposition by Integrating In Vitro and In Silico Methodology.” 2016. Thesis, University of California – San Francisco. Accessed January 23, 2021. http://www.escholarship.org/uc/item/5ds3q196.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Hosey, Chelsea Mariah. “Predicting Drug Disposition by Integrating In Vitro and In Silico Methodology.” 2016. Web. 23 Jan 2021.

Vancouver:

Hosey CM. Predicting Drug Disposition by Integrating In Vitro and In Silico Methodology. [Internet] [Thesis]. University of California – San Francisco; 2016. [cited 2021 Jan 23]. Available from: http://www.escholarship.org/uc/item/5ds3q196.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Hosey CM. Predicting Drug Disposition by Integrating In Vitro and In Silico Methodology. [Thesis]. University of California – San Francisco; 2016. Available from: http://www.escholarship.org/uc/item/5ds3q196

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Toronto

29. Crosby, Michael. Regulation of Hepatic CYP3A4 by 3-Methylcholanthrene in Humanized PXR-CAR-CYP3A4/3A7 Mice.

Degree: 2017, University of Toronto

URL: http://hdl.handle.net/1807/79379

►

Polycyclic aromatic hydrocarbons (PAHs) are environmental pollutants that activate the aryl hydrocarbon receptor, triggering many biological effects typified by induction of cytochrome P450 1A1 (CYP1A1).… (more)

Subjects/Keywords: aryl hydrocarbon receptor; Cyp3a11; drug metabolism; drug metabolizing enzyme; P450; polycyclic aromatic hydrocarbon; 0419

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Crosby, M. (2017). Regulation of Hepatic CYP3A4 by 3-Methylcholanthrene in Humanized PXR-CAR-CYP3A4/3A7 Mice. (Masters Thesis). University of Toronto. Retrieved from http://hdl.handle.net/1807/79379

Chicago Manual of Style (16^th Edition):

Crosby, Michael. “Regulation of Hepatic CYP3A4 by 3-Methylcholanthrene in Humanized PXR-CAR-CYP3A4/3A7 Mice.” 2017. Masters Thesis, University of Toronto. Accessed January 23, 2021. http://hdl.handle.net/1807/79379.

MLA Handbook (7^th Edition):

Crosby, Michael. “Regulation of Hepatic CYP3A4 by 3-Methylcholanthrene in Humanized PXR-CAR-CYP3A4/3A7 Mice.” 2017. Web. 23 Jan 2021.

Vancouver:

Crosby M. Regulation of Hepatic CYP3A4 by 3-Methylcholanthrene in Humanized PXR-CAR-CYP3A4/3A7 Mice. [Internet] [Masters thesis]. University of Toronto; 2017. [cited 2021 Jan 23]. Available from: http://hdl.handle.net/1807/79379.

Council of Science Editors:

Crosby M. Regulation of Hepatic CYP3A4 by 3-Methylcholanthrene in Humanized PXR-CAR-CYP3A4/3A7 Mice. [Masters Thesis]. University of Toronto; 2017. Available from: http://hdl.handle.net/1807/79379

University of Washington

30. Seguin, Ryan Patrick. Non-Dissociative Sequential Metabolism of Enoxacin to a Metabolic Intermediate Complex with Cytochrome P450 1A2.

Degree: PhD, 2017, University of Washington

URL: http://hdl.handle.net/1773/40646

► Cytochrome P450 enzymes constitute a superfamily of isoforms which accelerate the removal of foreign compounds from the body through oxidative biotransformation to generate polar metabolites… (more)

▼ Cytochrome P450 enzymes constitute a superfamily of isoforms which accelerate the removal of foreign compounds from the body through oxidative biotransformation to generate polar metabolites that are more readily excreted from the body. Hence, susceptibility to oxidation by cytochrome P450 may largely determine the in vivo half-life, plasma level, and tissue exposure of small molecule drugs. As the P450 isoforms involved in drug metabolism contain large, flexible, and promiscuous active sites which can bind and metabolize multiple drugs, it is common for one drug to interfere with the metabolism of another. Inhibition of a specific P450 isoform may lead to drug-drug interactions (DDIs) through impairment of metabolic clearance of a coadministered drug and the build-up of this drug or its metabolites to toxic levels in the body. The use of in vitro data to predict, rationalize and, ultimately, prevent DDIs is a top priority in drug development. Accordingly, emphasis in this field of study has been placed on understanding which drug structures inhibit P450 and the mechanism by which inhibition occurs. This dissertation explores the mechanism of inhibition of cytochrome P450 1A2 (CYP1A2) by the fluoroquinolone antibacterial enoxacin. Enoxacin elicits clinically-significant DDIs with theophylline and caffeine due to potent CYP1A2 inhibition in vivo. However, enoxacin is characterized as a weak reversible inhibitor of CYP1A2 in vitro leading to severe underprediction of the DDIs with theophylline and caffeine. Herein, we have clarified the mechanism of inhibition as a time-dependent irreversible process where enoxacin is sequentially metabolized within the CYP1A2 active site to a mechanism-based inhibitor. Thus, CYP1A2 is inactivated by a metabolite of enoxacin through formation of a metabolic-intermediate (MI) complex. The mechanism of MI complex formation requires N-hydroxylation of the piperazine ring of enoxacin followed by -carbon hydroxylation and oxidative ring-opening to a nitroso metabolite that strongly ligates to the ferrous heme iron of CYP1A2. We elucidated the mechanism of CYP1A2 inactivation as sequential metabolism of the piperazine ring to an MI complex in recombinant CYP1A2 and confirmed that this mechanism is still viable in human liver microsomes. Circumstantial evidence was provided for MI complex formation with CYP1A2 in primary human hepatocytes. The DDIs with theophylline and caffeine were well-predicted by in vitro to in vivo predictions using apparent CYP1A2 inactivation parameters for the parent drug, enoxacin. Our results suggest that enoxacin is sequentially metabolized to an MI complex non-dissociatively within the CYP1A2 active site and that released metabolite intermediates do not significantly contribute to MI complex formation. The non-dissociative nature of the sequential metabolic inactivation process accounts for our success in predicting the DDIs with theophylline and caffeine using apparent inactivation parameters of the parent drug. Although enoxacin requires multiple… Advisors/Committee Members: Kunze, Kent L (advisor).

Subjects/Keywords: Cytochrome P450; Drug-Drug Interactions; Drug Metabolism; Enoxacin; Fluoroquinolone; Mechanism-Based Inhibition; Pharmaceutical sciences; Medicinal chemistry

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Seguin, R. P. (2017). Non-Dissociative Sequential Metabolism of Enoxacin to a Metabolic Intermediate Complex with Cytochrome P450 1A2. (Doctoral Dissertation). University of Washington. Retrieved from http://hdl.handle.net/1773/40646

Chicago Manual of Style (16^th Edition):

Seguin, Ryan Patrick. “Non-Dissociative Sequential Metabolism of Enoxacin to a Metabolic Intermediate Complex with Cytochrome P450 1A2.” 2017. Doctoral Dissertation, University of Washington. Accessed January 23, 2021. http://hdl.handle.net/1773/40646.

MLA Handbook (7^th Edition):

Seguin, Ryan Patrick. “Non-Dissociative Sequential Metabolism of Enoxacin to a Metabolic Intermediate Complex with Cytochrome P450 1A2.” 2017. Web. 23 Jan 2021.

Vancouver:

Seguin RP. Non-Dissociative Sequential Metabolism of Enoxacin to a Metabolic Intermediate Complex with Cytochrome P450 1A2. [Internet] [Doctoral dissertation]. University of Washington; 2017. [cited 2021 Jan 23]. Available from: http://hdl.handle.net/1773/40646.

Council of Science Editors:

Seguin RP. Non-Dissociative Sequential Metabolism of Enoxacin to a Metabolic Intermediate Complex with Cytochrome P450 1A2. [Doctoral Dissertation]. University of Washington; 2017. Available from: http://hdl.handle.net/1773/40646

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Open Access Theses and Dissertations