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The effect of endogenous and exogenous chemicals on drug metabolizing enzymes and drug transporters in human hepatocytes

Ranade, Aarati Ram (2005) The effect of endogenous and exogenous chemicals on drug metabolizing enzymes and drug transporters in human hepatocytes. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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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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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Ranade, Aarati Ramarrst13@pitt.eduARRST13
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairVenkataramanan, Ramanrv@pitt.eduRV
Committee CoChairStrom, Stephen Cstrom@pitt.eduSTROM
Committee MemberDonnenberg, Albertdonnenbergad@MSX.UPMC.EDUDONNAL
Committee MemberVollmer, Regis Rvollm@pitt.eduVOLLM
Committee MemberVollmer, Regis Rvollm@pitt.eduVOLLM
Date: 21 December 2005
Date Type: Completion
Defense Date: 28 November 2005
Approval Date: 21 December 2005
Submission Date: 15 December 2005
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: School of Pharmacy > Pharmaceutical Sciences
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: cytokines; drug metabolism; drug transporters; HIV-protease inhibitors; human hepatocytes
Other ID:, etd-12152005-152206
Date Deposited: 10 Nov 2011 20:11
Last Modified: 19 Dec 2016 14:38


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