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Open Access Publications from the University of California

Scholarly Works (6 results)

  • Article
  • Peer Reviewed
Drug transporters are recognized as key players in the processes of drug absorption, distribution, metabolism, and elimination. The localization of uptake and efflux transporters in organs responsible for drug biotransformation and excretion gives transporter proteins a unique gatekeeper function in controlling drug access to metabolizing enzymes and excretory pathways. This review seeks to discuss the influence intestinal and hepatic drug transporters have on pharmacokinetic parameters, including bioavailability, exposure, clearance, volume of distribution, and half-life, for orally dosed drugs. This review also describes in detail the Biopharmaceutics Drug Disposition Classification System (BDDCS) and explains how many of the effects drug transporters exert on oral drug pharmacokinetic parameters can be predicted by this classification scheme.
    Cover page: The Role of Transporters in the Pharmacokinetics of Orally Administered Drugs
    • Article
    • Peer Reviewed
    UC San Francisco Previously Published Works (2009)
    Drug transporters are recognized as key players in the processes of drug absorption, distribution, metabolism, and elimination. The localization of uptake and efflux transporters in organs responsible for drug biotransformation and excretion gives transporter proteins a unique gatekeeper function in controlling drug access to metabolizing enzymes and excretory pathways. This review seeks to discuss the influence intestinal and hepatic drug transporters have on pharmacokinetic parameters, including bioavailability, exposure, clearance, volume of distribution, and half-life, for orally dosed drugs. This review also describes in detail the Biopharmaceutics Drug Disposition Classification System (BDDCS) and explains how many of the effects drug transporters exert on oral drug pharmacokinetic parameters can be predicted by this classification scheme.
      Cover page: The Role of Transporters in the Pharmacokinetics of Orally Administered Drugs
      • Thesis
      • Peer Reviewed
      UC San Francisco Electronic Theses and Dissertations (2010)

      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.

        Cover page: The Role of Transporters in the Absorption, Distribution, Metabolism and Excretion (ADME) of Orally Administered Drugs
        • Article
        • Peer Reviewed
        UC San Francisco Previously Published Works (2013)

        Objective

        Nevirapine is an important component of highly active antiretroviral therapy used in the treatment of HIV infection. There is a considerable variation in the pharmacokinetics of nevirapine and this variation can impact the efficacy and toxicity of nevirapine. Although some of this variation can be attributed to environmental factors, the degree to which heritability influences nevirapine pharmacokinetics is unknown. This study aims to estimate how much variation in nevirapine pharmacokinetics is due to genetic factors and to investigate the contribution of selected polymorphisms to this variability.

        Methods

        Two doses of immediate-release nevirapine were administered to European (n=11) and African American (n=6) participants recruited from the Research in Access to Care in the Homeless cohort. A repeated drug administration method was then used to determine the relative genetic contribution (r(GC)) to variability in nevirapine AUC(0-6 h). Nevirapine plasma levels were quantified using LC/MS/MS. Patients were also genotyped for selected polymorphisms in candidate genes that may influence nevirapine pharmacokinetics.

        Results

        A significant r(GC) for nevirapine AUC(0-6 h) was found in Europeans (P=0.02) and African Americans (P=0.01). A trend toward higher nevirapine AUC(0-6 h) for the CYP2B6 516TT (rs3745274; Q172H) genotype was observed in European Americans (P=0.19).

        Conclusion

        This study demonstrates that there is a significant genetic component to variability in nevirapine pharmacokinetics. Although genetic variants such as CYP2B6 polymorphisms attributed to some of this variation, these data suggest that there may be additional genetic factors that influence nevirapine pharmacokinetics.
          Cover page: Measuring the overall genetic component of nevirapine pharmacokinetics and the role of selected polymorphisms
          • Article
          • Peer Reviewed
          UC San Francisco Previously Published Works (2013)

          Objective

          Nevirapine is an important component of highly active antiretroviral therapy used in the treatment of HIV infection. There is a considerable variation in the pharmacokinetics of nevirapine and this variation can impact the efficacy and toxicity of nevirapine. Although some of this variation can be attributed to environmental factors, the degree to which heritability influences nevirapine pharmacokinetics is unknown. This study aims to estimate how much variation in nevirapine pharmacokinetics is due to genetic factors and to investigate the contribution of selected polymorphisms to this variability.

          Methods

          Two doses of immediate-release nevirapine were administered to European (n=11) and African American (n=6) participants recruited from the Research in Access to Care in the Homeless cohort. A repeated drug administration method was then used to determine the relative genetic contribution (r(GC)) to variability in nevirapine AUC(0-6 h). Nevirapine plasma levels were quantified using LC/MS/MS. Patients were also genotyped for selected polymorphisms in candidate genes that may influence nevirapine pharmacokinetics.

          Results

          A significant r(GC) for nevirapine AUC(0-6 h) was found in Europeans (P=0.02) and African Americans (P=0.01). A trend toward higher nevirapine AUC(0-6 h) for the CYP2B6 516TT (rs3745274; Q172H) genotype was observed in European Americans (P=0.19).

          Conclusion

          This study demonstrates that there is a significant genetic component to variability in nevirapine pharmacokinetics. Although genetic variants such as CYP2B6 polymorphisms attributed to some of this variation, these data suggest that there may be additional genetic factors that influence nevirapine pharmacokinetics.
            Cover page: Measuring the overall genetic component of nevirapine pharmacokinetics and the role of selected polymorphisms
            • Article
            • Peer Reviewed
            UC San Francisco Previously Published Works (2015)
            Susceptibility to quinoline antimalarial intoxication may reflect individual genetic and drug-induced variation in neuropharmacokinetics. In this report, we describe a case of chloroquine intoxication that appeared to be prolonged by subsequent use of multiple psychotropic medications. This case highlights important new considerations for the management of quinoline antimalarial intoxication.
              Cover page: Prolonged neuropsychiatric effects following management of chloroquine intoxication with psychotropic polypharmacy
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