International Conference on Drug-drug Interactions edition:12 location:Seattle date:25-27 May 2009
In the past decade, the important role of drug transporters in the disposition of xenobiotics has been demonstrated. In the liver, several families of drug transporters are expressed at the sinusoidal (basolateral) and canalicular (apical, to the bile) membrane domains. The cooperation between these drug transporters and the drug metabolizing enzymes, such as those belonging to the Cytochrome P450 family, reflects the drug detoxification function of the liver. With respect to hepatic uptake transporters (at the sinusoidal membrane), especially transport proteins supporting bile acid accumulation (such as NTCP, Na+-taurocholate cotransporting peptide) have been studied in detail. In addition, there has been much interest in gaining better understanding in the extact role of the hepatic isoforms of the OATP (Organic Anion Transporting Polypeptide) family of transporters in hepatic drug accumulation. Recently, increasing evidence is supporting the concept that OATPs are rate-limiting in the hepatic elimination of many marketed drugs (e.g. HIV protease inhibitors). This finding implies that OATPs may also be mediating drug interactions, and many drugs were already found to inhibit OATP-mediated transport of endogenous compounds as well as xenobiotics.
In this presentation, the utility of suspended as well as sandwich-cultured human hepatocytes for studying OATP-mediated drug accumulation will be illustrated. New data on donor-related variability in hepatic accumulation of transporter substrates will be shown. In addition, the utility of these in vitro systems to study transporter-mediated drug interactions will be clarified. Recent data obtained in our lab indicate the promising potential of human hepatocytes from cryopreserved sources to study hepatic drugs transport. Data comparing drug transporter activities in freshly-isolated versus cryopreserved hepatocytes will be provided. Finally, the importance of using hepatocytes from human origin to study drug interactions will be demonstrated by sharing recent data on substantial species differences in drug interaction profiles of HIV protease inhibitors.