PBPK modeling of irbesartan: incorporation of hepatic uptake
| Autor: | Helene, Chapy, Sylvie, Klieber, Priscilla, Brun, Sabine, Gerbal-Chaloin, Xavier, Boulenc, Olivier, Nicolas |
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| Rok vydání: | 2015 |
| Předmět: |
Adult
Glycosylation Liver-Specific Organic Anion Transporter 1 Biphenyl Compounds Blotting Western Primary Cell Culture Organic Anion Transporters Tetrazoles Irbesartan Organic Anion Transporters Sodium-Independent Transfection Models Biological Kinetics Solute Carrier Organic Anion Transporter Family Member 1B3 HEK293 Cells Liver Tandem Mass Spectrometry Hepatocytes Humans Computer Simulation Angiotensin II Type 1 Receptor Blockers Cells Cultured Chromatography Liquid |
| Zdroj: | Biopharmaceuticsdrug disposition. 36(8) |
| ISSN: | 1099-081X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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