title: PBPK modeling of irbesartan: incorporation of hepatic uptake.
abstract: Physiological based pharmacokinetic (PBPK) modeling is now commonly used in drug development to integrate human or animal physiological data in order to predict pharmacokinetic profiles. The aim of this work was to construct and refine a PBPK model of irbesartan taking into account its active uptake via OATP1B1/B3 in order to predict more accurately its pharmacokinetic profile using Simcyp(®). The activity and expression of the human hepatocyte transporters OATP1B1 and OATP1B3 were studied. The relative activity factors (RAFs) for OATP1B1 and OATP1B3 transporters were calculated from intrinsic clearances obtained by concentration dependent uptake experiments in human hepatocytes and HEK overexpressing cells: RAF1B1 using estrone-3-sulfate and pitavastatine clearances, and RAF1B3 using cholecystokinine octapeptide (CCK-8) clearances. The relative expression factor (REF) was calculated by comparing immunoblotting of hepatocytes (REFHH ) or tissues (REFtissue) with those of overexpressing HEK cells for each transporter. These scaling factors were applied in a PBPK model of irbesartan using the Simcyp® simulator. Pharmacokinetic simulation using REFHH (1.82 for OATP1B1, 8.03 for OATP1B3) as an extrapolation factor was the closest to the human clinical pharmacokinetic profile of irbesartan. These investigations show the importance of integrating the contribution of the active uptake of a drug in the liver to improve PBPK modeling.
authors.affiliation: Drug Disposition Domain, Disposition Safety and Animal Research, Sanofi, Montpellier, France.
authors.forename: Helene
authors.initials: H
authors.lastname: Chapy
authors.affiliation: Drug Disposition Domain, Disposition Safety and Animal Research, Sanofi, Montpellier, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Klieber
authors.affiliation: Drug Disposition Domain, Disposition Safety and Animal Research, Sanofi, Montpellier, France.
authors.forename: Priscilla
authors.initials: P
authors.lastname: Brun
authors.affiliation: INSERM, U1040, Institut de Recherche en Biothérapie, Montpellier, F-34293, France.|Université Montpellier 1, UMR 1040, Montpellier, F-34293, France.
authors.forename: Sabine
authors.initials: S
authors.lastname: Gerbal-Chaloin
authors.affiliation: Drug Disposition Domain, Disposition Safety and Animal Research, Sanofi, Montpellier, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Boulenc
authors.affiliation: Drug Disposition Domain, Disposition Safety and Animal Research, Sanofi, Montpellier, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Nicolas
mesh_terms: D000328:Adult; D047228:Angiotensin II Type 1 Receptor Blockers / Q000493:pharmacokinetics*; D001713:Biphenyl Compounds / Q000493:pharmacokinetics*; D015153:Blotting, Western; D002478:Cells, Cultured; D002853:Chromatography, Liquid; D003198:Computer Simulation; D006031:Glycosylation; D057809:HEK293 Cells; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D000077405:Irbesartan; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D027381:Liver-Specific Organic Anion Transporter 1; D008954:Models, Biological; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics / Q000378:metabolism; D061251:Primary Cell Culture; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D053719:Tandem Mass Spectrometry; D013777:Tetrazoles / Q000493:pharmacokinetics*; D014162:Transfection
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001713:Biphenyl Compounds; D027381:Liver-Specific Organic Anion Transporter 1; 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; D013777:Tetrazoles; D000077405:Irbesartan
keywords: OATP; PBPK; irbesartan; scaling factor; transporter