Over the last two decades drug tranporter proteins have been the focus of increased study to determine their roles in drug pharmacokinetics and pharmacodynamics. Their importance is increasingly recognized by regulatory agencies, the drug development industry, and the medical community. Although a great deal of progress has been made in the field, the finer nuances and full range of transporter influence and function is still an important area of investigation.
My dissertation research investigated the role of transporters on drug ADME properties in a variety of systems, including stably transfected cells, isolated rat and human hepatocytes, the isolated perfused rat liver (IPRL) system, isolated rat jejunal segments, and a human clinical study. Transfected cells and the IPRL system were used to examine the ability of the Organic Anion Transporting Polypeptides (OATP/Oatp) to efflux drugs out of cells with inconclusive results. Transfected cells and isolated rat jejunal segments were used to study the interplay of the Breast Cancer Resistance Protein (BCRP/Bcrp) with intestinal drug metabolizing enzymes, again with inconclusive results. Transfected cells and isolated rat and human hepatocytes were used to determine whether or not warfarin or phenytoin are substrates for hepatic uptake transporters. Significant inhibition of warfarin uptake by the OATP/Oatp inhibitor rifampin was seen, but further studies with OATP1B1 and OATP2B1-expressing cells indicated that neither of these isoforms are responsible for warfarin uptake. No inhibitable uptake of phenytoin was seen in hepatocytes or in transfected cells. A human clinical study was conducted to determine the effect of hepatic OATP inhibition on warfarin pharmacokinetics with the result that OATP inhibition did not increase warfarin plasma levels as would be expected if hepatic OATP uptake was an important factor in warfarin disposition. Transfected cells were used to explore possible transporter-based mechanisms for the drug-drug interactions seen between raltegravir and immunosuppressants. The experiments indicated that while this was an unlikely mechanism for the specific interactions seen, raltegravir did interact significantly with hepatic uptake and efflux transporters.
|Advisor:||Benet, Leslie Z.|
|Commitee:||Giacomini, Kathleen M., Huang, Yong|
|School:||University of California, San Francisco|
|Department:||Pharmaceutical Sciences and Pharmacogenomics|
|School Location:||United States -- California|
|Source:||DAI-B 71/02, Dissertation Abstracts International|
|Keywords:||Metabolism, Oral drugs, Pharmacokinetics, Transporters|
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