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AN ASSESSMENT OF THE POTENTIAL INFLUENCE OF BEXAROTENE, A NOVEL RETINOID X RECEPTOR AGONIST, ON THE HEPATIC METABOLISM OF BEXAROTENE

SHROFF, PURVI B

Abstract Details

2005, MS, University of Cincinnati, Pharmacy : Pharmaceutical Sciences.
Background: Bexarotene, a novel RXR agonist, is used in the treatment of cutaneous T cell lymphoma and is under investigation for the treatment of solid tumors in combination with other chemotherapeutic agents including docetaxel. Both docetaxel and bexarotene are metabolized by CYP3A4 and in animal studies bexarotene has been shown to enhance the activity of CYP3A enzymes and increase its content. Thus, there exists a potential for interactions between these two agents, which was evaluated in this study. Method: Bexarotene from commercial capsules was dissolved in DMSO. Employing pooled human liver microsomes, we assessed the influence of bexarotene on the metabolism of docetaxel. Microsomal fractions (1mg protein) were incubated with bexarotene (0.1 – 10µM) and docetaxel (0.5 – 5µM) in the presence of NADPH (1 mM). Using liquid-liquid extraction, unreacted docetaxel was extracted and levels were measured using a validated HPLC method. Next, we employed primary human hepatocytes to assess the inductive effects of bexarotene. Hepatocytes were treated with bexarotene (1 – 50µM) for 72 hours. Docetaxel metabolism by microsomal fractions was then evaluated. Testosterone 6â-hydroxylation and CYP3A4- specific protein and mRNA levels were also measured to evaluate whether bexarotene acts as an inducer of CYP3A4. Results: Bexarotene, at clinically relevant concentrations (1-10µM) did not inhibit docetaxel metabolism. Also, incubation of primary human hepatocytes with bexarotene did not enhance docetaxel metabolism, which was consistent with the observation that the testosterone 6â-hydroxylation and CYP3A4 expression in bexarotene – treated cells were not statistically different than those from untreated cells. Conclusions: Our findings suggest that bexarotene is unlikely to alter hepatic metabolism of docetaxel. Bexarotene appears to exhibit species – specific differences in the induction of CYP3A and further studies are required to understand the mechanistic basis of these differences.
Pankaj Desai (Advisor)
94 p.

Recommended Citations

Citations

  • SHROFF, P. B. (2005). AN ASSESSMENT OF THE POTENTIAL INFLUENCE OF BEXAROTENE, A NOVEL RETINOID X RECEPTOR AGONIST, ON THE HEPATIC METABOLISM OF BEXAROTENE [Master's thesis, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1123813553

    APA Style (7th edition)

  • SHROFF, PURVI. AN ASSESSMENT OF THE POTENTIAL INFLUENCE OF BEXAROTENE, A NOVEL RETINOID X RECEPTOR AGONIST, ON THE HEPATIC METABOLISM OF BEXAROTENE. 2005. University of Cincinnati, Master's thesis. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1123813553.

    MLA Style (8th edition)

  • SHROFF, PURVI. "AN ASSESSMENT OF THE POTENTIAL INFLUENCE OF BEXAROTENE, A NOVEL RETINOID X RECEPTOR AGONIST, ON THE HEPATIC METABOLISM OF BEXAROTENE." Master's thesis, University of Cincinnati, 2005. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1123813553

    Chicago Manual of Style (17th edition)