Estimating In Vivo Fractional Contribution of OATP1B1 to Human Hepatic Active Uptake by Mechanistically Modeling Pharmacogenetic Data.

A reasonable estimate on the fractional contribution of transporters to total hepatic active uptake (F _T ) is a critical factor in understanding and predicting human clearance, drug-drug interaction, and pharmacokinetic variability for hepatic transporter substrates. F _T values for organic-anion-transporting polypeptide (OATP) 1B1 have been previously determined using in vitro assays. However, to date, none of the published in vitro F _T values has been validated against or compared with in vivo F _T values due to the lack of clinical data from selective substrates or inhibitors. The possible transporter-dependent in vitro to in vivo scaling further weakens the predictive power of these in vitro-determined F _T values. In facing this challenge, a method is developed in this study to estimate in vivo OATP1B1 F _T values by mechanistically modeling genotyped clinical pharmacokinetic data. The method is based on the hypothesis that observed change in hepatic active uptake clearance due to OATP1B1 polymorphism depends on two factors: (1) the contribution of OATP1B1 to the hepatic active uptake clearance and (2) the change of OATP1B1-mediated intrinsic uptake activity by the polymorphism. Conversely, if the changes caused by genetic variations in hepatic active uptake clearance and in OATP1B1-mediated clearance are known, then the OATP1B1 contribution to the hepatic active uptake clearance can be calculated. This is the first time that in vivo hepatic transporter F _T values and a method to estimate these values are reported. Both F _T values and the estimation method will facilitate future understanding and prediction on the transporter-mediated drug disposition.