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

AbstractA reasonable estimate on the fractional contribution of transporters to total hepatic active uptake (FT) is a critical factor in understanding and predicting human clearance, drug-drug interaction, and pharmacokinetic variability for hepatic transporter substrates.FT values for organic-anion-transporting polypeptide (OATP) 1B1 have been previously determined usingin vitro assays. However, to date, none of the publishedin vitro FT values has been validated against or compared within vivo FT values due to the lack of clinical data from selective substrates or inhibitors. The possible transporter-dependentin vitro toin vivo scaling further weakens the predictive power of thesein vitro–determinedFT values. In facing this challenge, a method is developed in this study to estimatein vivo OATP1B1FT 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 thatin vivo hepatic transporterFT values and a method to esti...
Source: The AAPS Journal - Category: Drugs & Pharmacology Source Type: research