Cyclosporine Inhibition of Hepatic and Intestinal CYP3A4, Uptake and Efflux Transporters: Application of PBPK Modeling in the Assessment of Drug-drug Interaction Potential

Overview

Journal Pharm Res

Specialties Pharmacology
Pharmacy

Date 2012 Nov 27

PMID 23179780

Citations 46

Authors

Michael Gertz

Catherine M Cartwright

Michael J Hobbs

Kathryn E Kenworthy

Malcolm Rowland

J Brian Houston

Aleksandra Galetin

Affiliations

Soon will be listed here.

Abstract

Purpose: To apply physiologically-based pharmacokinetic (PBPK) modeling to investigate the consequences of reduction in activity of hepatic and intestinal uptake and efflux transporters by cyclosporine and its metabolite AM1.

Methods: Inhibitory potencies of cyclosporine and AM1 against OATP1B1, OATP1B3 and OATP2B1 were investigated in HEK293 cells +/- pre-incubation. Cyclosporine PBPK model implemented in Matlab was used to assess interaction potential (+/- metabolite) against different processes (uptake, efflux and metabolism) in liver and intestine and to predict quantitatively drug-drug interaction with repaglinide.

Results: Cyclosporine and AM1 were potent inhibitors of OATP1B1 and OATP1B3, IC(50) ranging from 0.019-0.093 μM following pre-incubation. Cyclosporine PBPK model predicted the highest interaction potential against liver uptake transporters, with a maximal reduction of >70% in OATP1B1 activity; the effect on hepatic efflux and metabolism was minimal. In contrast, 80-97% of intestinal P-gp and CYP3A4 activity was reduced due to the 50-fold higher cyclosporine enterocytic concentrations relative to unbound hepatic inlet. The inclusion of AM1 resulted in a minor increase in the predicted maximal reduction of OATP1B1/1B3 activity. Good predictability of cyclosporine-repaglinide DDI and the impact of dose staggering are illustrated.

Conclusions: This study highlights the application of PBPK modeling for quantitative prediction of transporter-mediated DDIs with concomitant consideration of P450 inhibition.

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