Relative Activity Factor (RAF)-Based Scaling of Uptake Clearance Mediated by Organic Anion Transporting Polypeptide (OATP) 1B1 and OATP1B3 in Human Hepatocytes

Abstract

In vitro-in vivo extrapolation based on uptake clearance determined in human hepatocytes has been used to predict in vivo hepatic clearance of organic anion transporting polypeptide (OATP) substrates. This study evaluated the relative activity factor (RAF) approach to extrapolate active uptake clearance in transporter-transfected cell systems (CL) to that in human hepatocyte suspensions (PS). RAF values for OATP1B1 and OATP1B3 were determined in two batches of cryopreserved human hepatocytes using estrone-3-sulfate and cholecystokinin octapeptide as reference substrates, respectively. Fourteen OATP1B substrate drugs selected (atorvastatin, bosentan, cerivastatin, fexofenadine, fluvastatin, glibenclamide, irbesartan, nateglinide, pitavastatin, pravastatin, rosuvastatin, telmisartan, torasemide, and valsartan) showed temperature-dependent uptake in human hepatocytes. In transporter-transfected cells, OATP1B1- and OATP1B3-mediated uptake was observed in all compounds except for telmisartan. RAF-based net CL was mainly accounted for by OATP1B1 (72.3-99.7%) and fell within the 3-fold of PS observed in human hepatocytes in 11 out of 13 compounds (excluding telmisartan). This study demonstrated that the RAF approach provides a quantitative index of OATP1B1- and OATP1B3-mediated PS in human hepatocytes, which will facilitate the optimization of the pharmacokinetic properties of OATP1B substrates at nonclinical stages of drug development.

Novel testing strategy for prediction of rat biliary excretion of intravenously administered estradiol-17β glucuronide

“…This also holds for their use to mimic biliary transport of other substrates for Oatps and substrates for other hepatic transporters (Oat2 and Oct1) involved in biliary excretion. To this end similar studies with other substrates for Oatps such as statins and ACE inhibitors (Izumi et al 2018;Watanabe et al 2010) or for other hepatic transporters such as antineoplastic drugs, antivirals. antidiuretics and some alkaloids (Burckhardt 2012;Lozano et al 2013;Marada et al 2015) may be of use.…”

“…To solve this matter a relative expression factor (REF) can be used (Chan et al 2019;Jamei et al 2014). Moreover, because the activity of the transporter in the transfected cell can differ from its in vivo activity often a relative activity factor (RAF) is used as well (Izumi et al 2018;Poirier et al 2009). Other factors may further complicate this in vitro to in vivo scaling, such as the fact that the cell of origin used to generate the transfected cell model [e.g.…”

Hepatic transporter‐mediated pharmacokinetic drug–drug interactions: Recent studies and regulatory recommendations

“…IVIVE‐based determination of uptake clearance in human hepatocytes was demonstrated as better metrics for the estimation of total hepatic intrinsic clearance than the human microsomal metabolic clearance data. However, the high cost of in vitro tools and limited availability of human hepatocytes showing transporter activities, and inter‐batch differences in the uptake activity should be considered (Izumi et al., 2018).…”

Examination of Physiologically‐Based Pharmacokinetic Models of Rosuvastatin

“…Instead of using the global CL int,T determined from fitting in vivo data and assigning percentages to each hepatic uptake transporter involved for input, M‐IV used in vitro transporter data and scaled the data up to predict in vivo values. The CL int from a suspension hepatocyte study with and without sodiuM‐containing buffer was input for NTCP, 48 while J max and K m values from HEK293 cells overexpressing transporters were input for OATP1B1, 1B3, and 2B1 45,49 . MRP4 was included for sinusoidal efflux as it was with M‐III, but instead of model fitting to obtain a value, here experimental J max and K m values from membrane vesicles were input 47 .…”