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.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-12152005-152206 |
| Date | 21 December 2005 |
| Creators | Ranade, Aarati Ram |
| Contributors | Regis R. Vollmer, Ph.D., Raman Venkataramanan, Ph.D., Stephen C. Strom, Ph.D., Albert Donnenberg, Ph.D., Reginald F. Frye, Ph.D. |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-12152005-152206/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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