Type of Document	Dissertation
Author	Ranade, Aarati Ram
URN	etd-12152005-152206
Title	The effect of endogenous and exogenous chemicals on drug metabolizing enzymes and drug transporters in human hepatocytes
Degree	Doctor of Philosophy
Program	Pharmaceutical Sciences
School	School of Pharmacy
Advisory Committee	Advisor Name Title Raman Venkataramanan, Ph.D. Committee Chair Stephen C. Strom, Ph.D. Committee Co-Chair Albert Donnenberg, Ph.D. Committee Member Reginald F. Frye, Ph.D. Committee Member Regis R. Vollmer, Ph.D. Committee Member
Keywords	cytokines drug transporters HIV-protease inhibitors drug metabolism human hepatocytes
Date of Defense	2005-11-28
Availability	restricted
Abstract Significant variability in the pharmacokinetics of drugs such as cyclosporine, tacrolimus, sirolimus and mycophenolic acid, is seen in liver transplant patients. These agents are primarily metabolized by CYP3A4 or UGT1A1, and are also substrates for drug transporters such as P-glycoprotein, multidrug resistance protein 2 (MRP2) and bile salt export pump (BSEP). Factors modulating the expression and activity of these enzymes and transporters will lead to changes in the clearance of immunosuppressive agents. Inflammation associated with infection or organ rejection after transplantation can modulate the expression and activity of CYP3A4, UGT1A1 and various drug transporters. HIV-protease inhibitors (HIV-PIs) used for the treatment of HIV infection are shown to modulate the blood levels of immunosuppressive agents. The primary goal of this dissertation research was to evaluate the effect of endogenous chemicals such as cytokines and exogenous compounds such as HIV-protease inhibitors on human hepatic drug metabolizing enzymes and transporters using primary cultures of human hepatocytes. The results from this research indicate that HIV-protease inhibitors generally decrease CYP3A4 activity inspite of increasing CYP3A4 mRNA and protein. The effect of PIs on CYP3A4 recovers over time. PIs also increased UGT1A1 mediated metabolism as well as mRNA expression of transporters. These effects are dependent on the HIV-protease inhibitor used and its concentration. Additionally, HIV-PIs increased the expression and activity of hepatic efflux transporters. These effects of HIV-PIs are found to be potentially mediated through alteration in PXR and CAR expression. Cytokines, released during infection or inflammation process, were observed to downregulate the expression and activity of UGTs and transporters through modulation of PXR and CAR.
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