title: Prediction of organic anion-transporting polypeptide 1B1- and 1B3-mediated hepatic uptake of statins based on transporter protein expression and activity data.
abstract: Organic anion-transporting polypeptides (OATP) 1B1 and OATP1B3 are drug transporters mediating the active hepatic uptake of their substrates. Because they exhibit overlapping substrate specificities, the contribution of each isoform to the net hepatic uptake needs to be considered when predicting drug-drug interactions. The relative contribution of OATP1B1- and OATP1B3-mediated uptake of statins into hepatocytes was estimated based on either relative transporter protein expression data or relative activity data. Therefore, kinetics of eight statins and OATP1B1- and OATP1B3-specific reference substrates was determined in OATP1B1- and OATP1B3-expressing human embryonic kidney 293 cells and in human cryopreserved hepatocytes. Absolute OATP1B1 and OATP1B3 protein abundance was determined by liquid chromatography-tandem mass spectrometry in all expression systems. Transporter activity data generated in recombinant cell lines were extrapolated to hepatocyte values using relative transporter expression factors (REF) or relative activity factors (RAF). Our results showed a pronounced OATP1B1 and comparatively low OATP1B3 protein expression in the investigated hepatocyte lot. Based on REF scaling, we demonstrated that the active hepatic uptake clearances of reference substrates, atorvastatin, pravastatin, rosuvastatin, and simvastatin were well predicted within twofold error, demonstrating that OATP1B1 and OATP1B3 were major contributors. For other statins, the net hepatic uptake clearance was underpredicted, suggesting the involvement of other hepatic uptake transporters. Summarized, we showed that REF- and RAF-based predictions were highly similar, indicating a direct transporter expression-activity relationship. Moreover, we demonstrated that the REF-scaling method provided a powerful tool to quantitatively assess the transporter-specific contributions to the net uptake clearance of statins in hepatocytes.
authors.affiliation: Division of Drug Metabolism and Pharmacokinetics, Drug-Drug Interactions Section, Novartis Institutes for BioMedical Research, Basel, Switzerland (A.K., G.C., B.P.); and Department of Pharmaceutical Sciences, Division of Pharmaceutical Technology, University of Basel, Basel, Switzerland (A.K., J.H.).
authors.forename: Annett
authors.initials: A
authors.lastname: Kunze
authors.affiliation: Division of Drug Metabolism and Pharmacokinetics, Drug-Drug Interactions Section, Novartis Institutes for BioMedical Research, Basel, Switzerland (A.K., G.C., B.P.); and Department of Pharmaceutical Sciences, Division of Pharmaceutical Technology, University of Basel, Basel, Switzerland (A.K., J.H.).
authors.forename: Jörg
authors.initials: J
authors.lastname: Huwyler
authors.affiliation: Division of Drug Metabolism and Pharmacokinetics, Drug-Drug Interactions Section, Novartis Institutes for BioMedical Research, Basel, Switzerland (A.K., G.C., B.P.); and Department of Pharmaceutical Sciences, Division of Pharmaceutical Technology, University of Basel, Basel, Switzerland (A.K., J.H.).
authors.forename: Gian
authors.initials: G
authors.lastname: Camenisch
authors.affiliation: Division of Drug Metabolism and Pharmacokinetics, Drug-Drug Interactions Section, Novartis Institutes for BioMedical Research, Basel, Switzerland (A.K., G.C., B.P.); and Department of Pharmaceutical Sciences, Division of Pharmaceutical Technology, University of Basel, Basel, Switzerland (A.K., J.H.) birk.poller@novartis.com.
authors.forename: Birk
authors.initials: B
authors.lastname: Poller
mesh_terms: D001692:Biological Transport / Q000502:physiology; D002460:Cell Line; D004347:Drug Interactions / Q000502:physiology; D057809:HEK293 Cells; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D027381:Liver-Specific Organic Anion Transporter 1; D026901:Membrane Transport Proteins / Q000378:metabolism; D027361:Organic Anion Transporters / Q000378:metabolism*; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism*; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D027381:Liver-Specific Organic Anion Transporter 1; D026901:Membrane Transport Proteins; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; C503999:SLCO1B1 protein, human; C421209:SLCO1B3 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3