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You searched for +publisher:"The Ohio State University" +contributor:("Phelps, Mitch"). Showing records 1 – 2 of 2 total matches.

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The Ohio State University

1. Ni, Wenjun. Pharmacokinetic-Pharmacodynamic and Pharmacogenetic Studies of Flavopiridol and its Glucuronide Metabolite.

Degree: PhD, Pharmacy, 2011, The Ohio State University

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in Western world. Flavopiridol (Alvocidib, NSC 649890), as a pan cyclin-dependent kinases inhibitor (CDKI), initiates cell cycle arrest and p53-independent apoptosis through down-regulation of Mcl-1 and X-linked inactivator of apoptosis (XIAP). A novel pharmacokinetically (PK)-based dosing schedule with a 30-minute intravenous bolus loading dose (IVB) followed by a 4-hour continuous intravenous infusion (CIVI) in patients with refractory CLL produced an approximately 50% overall response rate. A major flavopiridol metabolite, flavopiridol glucuronide (flavo-G), was as also evaluated in this study. In order to fully understand the inter-individual variability between patients, a phase 1 CLL patient data set (OSU0055) was evaluated and a two-compartment flavopiridol PK model followed by first-order elimination was developed by nonlinear mixed effects modeling. Bilirubin level was shown as a significant covariate, and OATP1B1 was first time discovered having a significant correlation with flavopiridol PK parameters. A functional analysis in vitro study was done to confirm that flavopiridol and flavo-G are substrates of OATP1B1. Since cellular redox status is important on cell survival and previous studies showed that flavopiridol can induce the decrease of intracellular GSH levels in transformed cells, glutathione (GSH) level was evaluated among leukemia cell models and patient’s CLL cells. The change in GSH level compared to baseline after flavopiridol treatment varied among cell models and individual patient. In order to evaluate flavo-G with flavopiridol treatment, a linked parent-metabolite population PK model was developed. This model was expanded to include a pharmacodynamic logistic-regression component linked to flavopiridol exposure level. This developing PK-PD-PG model of flavopiridol will help to characterize the factors associated with inter-individual variability in drug disposition and outcomes, and provide us better understanding of the mechanisms and factors governing the balance between safety and efficacy. Advisors/Committee Members: Phelps, Mitch A. (Committee Chair).

Subjects/Keywords: Pharmaceuticals; Pharmacy Sciences; Chronic lymphocytic leukemia; cyclin-dependent kinase inhibitor; pharmacokinetics; pharmacodynamics; pharmacogenetics; drug transporters; OATP1B1; glutathionep

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

APA (6th Edition):

Ni, W. (2011). Pharmacokinetic-Pharmacodynamic and Pharmacogenetic Studies of Flavopiridol and its Glucuronide Metabolite. (Doctoral Dissertation). The Ohio State University. Retrieved from http://rave.ohiolink.edu/etdc/view?acc_num=osu1299680524

Chicago Manual of Style (16th Edition):

Ni, Wenjun. “Pharmacokinetic-Pharmacodynamic and Pharmacogenetic Studies of Flavopiridol and its Glucuronide Metabolite.” 2011. Doctoral Dissertation, The Ohio State University. Accessed June 16, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=osu1299680524.

MLA Handbook (7th Edition):

Ni, Wenjun. “Pharmacokinetic-Pharmacodynamic and Pharmacogenetic Studies of Flavopiridol and its Glucuronide Metabolite.” 2011. Web. 16 Jun 2019.

Vancouver:

Ni W. Pharmacokinetic-Pharmacodynamic and Pharmacogenetic Studies of Flavopiridol and its Glucuronide Metabolite. [Internet] [Doctoral dissertation]. The Ohio State University; 2011. [cited 2019 Jun 16]. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=osu1299680524.

Council of Science Editors:

Ni W. Pharmacokinetic-Pharmacodynamic and Pharmacogenetic Studies of Flavopiridol and its Glucuronide Metabolite. [Doctoral Dissertation]. The Ohio State University; 2011. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=osu1299680524


The Ohio State University

2. Rozewski, Darlene M. Pharmacokinetics and P-glycoprotein-Mediated Transport of the Leading IMiDs in Mice.

Degree: PhD, Pharmacy, 2012, The Ohio State University

Lenalidomide and pomalidomide belong to a novel class of immunomodulatory (IMiD) drugs and have anti-angiogenic, anti-inflammatory, pro-erythropoietic and further anti-cancer activities. Both agents have shown promising therapeutic efficacy in multiple clinical applications, and lenalidomide has been approved by the United States Food and Drug Administration for use in multiple myeloma and myelodysplastic syndrome. Although many therapeutic activities have been discovered, the exact mechanistic targets of these agents remain to be elucidated and the mechanisms responsible for adverse effects are unknown. Additionally, transporters responsible for IMiD disposition, absorbance and clearance have not yet been identified. The use of animals in this regard may prove beneficial. However, pharmacokinetic evaluations necessary for these studies are absent from the literature. Herein, we (1) validate a method for lenalidomide quantification in murine plasma and tissues and verify application of the method to those of dosed mice, (2) perform a full comprehensive pharmacokinetic evaluation of lenalidomide in mice to classify dose linearity, intraperitoneal and oral bioavailability, and tissue disposition following multiple intravenous doses, (3) perform a pharmacokinetic evaluation of pomalidomide in mice following intravenous and oral administration and provide evidence of IMiD transport through the ABC efflux transporter P-glycoprotein. Advisors/Committee Members: Phelps, Mitch (Committee Co-Chair), Johnson, Amy (Committee Co-Chair), Byrd, John (Advisor).

Subjects/Keywords: Pharmaceuticals; Lenalidomide; Pharmacokinetics; Mouse; P-glycoprotein; Disposition; Bioavailability; Transporter

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

APA (6th Edition):

Rozewski, D. M. (2012). Pharmacokinetics and P-glycoprotein-Mediated Transport of the Leading IMiDs in Mice. (Doctoral Dissertation). The Ohio State University. Retrieved from http://rave.ohiolink.edu/etdc/view?acc_num=osu1331144282

Chicago Manual of Style (16th Edition):

Rozewski, Darlene M. “Pharmacokinetics and P-glycoprotein-Mediated Transport of the Leading IMiDs in Mice.” 2012. Doctoral Dissertation, The Ohio State University. Accessed June 16, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=osu1331144282.

MLA Handbook (7th Edition):

Rozewski, Darlene M. “Pharmacokinetics and P-glycoprotein-Mediated Transport of the Leading IMiDs in Mice.” 2012. Web. 16 Jun 2019.

Vancouver:

Rozewski DM. Pharmacokinetics and P-glycoprotein-Mediated Transport of the Leading IMiDs in Mice. [Internet] [Doctoral dissertation]. The Ohio State University; 2012. [cited 2019 Jun 16]. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=osu1331144282.

Council of Science Editors:

Rozewski DM. Pharmacokinetics and P-glycoprotein-Mediated Transport of the Leading IMiDs in Mice. [Doctoral Dissertation]. The Ohio State University; 2012. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=osu1331144282

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