Prediction of Cyclosporin-Mediated Drug Interaction Using Physiologically Based Pharmacokinetic Model Characterizing Interplay of Drug Transporters and Enzymes.

Yiting Yang,Ping Li,Li Liu,Zhongjian Wang,Xiaodong Liu,Zexin Zhang

doi:10.3390/ijms21197023

Abstract

Uptake transporter organic anion transporting polypeptides (OATPs), efflux transporters (P-gp, BCRP and MRP2) and cytochrome P450 enzymes (CYP450s) are widely expressed in the liver, intestine or kidney. They coordinately work to control drug disposition, termed as “interplay of transporters and enzymes”. Cyclosporine A (CsA) is an inhibitor of OATPs, P-gp, MRP2, BCRP and CYP3As. Drug–drug interaction (DDI) of CsA with victim drugs occurs via disordering interplay of transporters and enzymes. We aimed to establish a whole-body physiologically-based pharmacokinetic (PBPK) model which predicts disposition of CsA and nine victim drugs including atorvastatin, cerivastatin, pravastatin, rosuvastatin, fluvastatin, simvastatin, lovastatin, repaglinide and bosentan, as well as drug–drug interactions (DDIs) of CsA with nine victim drugs to investigate the integrated effect of enzymes and transporters in liver, intestinal and kidney on drug disposition. Predictions were compared with observations. Most of the predictions were within 0.5–2.0 folds of observations. Atorvastatin was represented to investigate individual contributions of transporters and CYP3As to atorvastatin disposition and their integrated effect. The contributions to atorvastatin disposition were hepatic OATPs >> hepatic CYP3A > intestinal CYP3As ≈ efflux transporters (P-gp/BCRP/MRP2). The results got the conclusion that the developed PBPK model characterizing the interplay of enzymes and transporters was successfully applied to predict the pharmacokinetics of 10 OATP substrates and DDIs of CsA with 9 victim drugs.

Highlights

Drug influx transporters, efflux transporters and metabolic enzymes such as cytochrome P450 enzymes (CYP450s) and UDP-glucuronosyltransferases (UGTs) are widely expressed in the liver, intestine or kidney
Hepatic uptake of these drugs is mainly mediated by hepatic organic anion transporting polypeptides (OATPs), which leads to high Kp values of drugs, metabolized by CYP450s and biliary or renal excretion via a P-gp, breast cancer resistance protein (BCRP) or MRP2-dependent mechanism
The results demonstrated that no considering inhibitions of cyclosporin A (CsA) on CYP3A-mediated metabolism and integrated effects occurring in the liver or intestine led to remarkably lower concentrations of atorvastatin compared with actual concentrations of atorvastatin when co-administrated CsA

Summary

Introduction

Efflux transporters and metabolic enzymes such as cytochrome P450 enzymes (CYP450s) and UDP-glucuronosyltransferases (UGTs) are widely expressed in the liver, intestine or kidney. Accumulating evidences have demonstrated that coadministration of CsA may lead potential drug–drug interactions (DDIs) with victim drug such as atorvastatin [14,15,16], cerivastatin [17], pravastatin [18,19], rosuvastatin [20], fluvastatin [21], simvastatin [22], lovastatin [18], repaglinide [23] and bosentan [24] via inhibiting these transporters or CYP3A4 Hepatic uptake of these drugs is mainly mediated by hepatic OATPs, which leads to high Kp values of drugs, metabolized by CYP450s (main CYP3A4) and biliary or renal excretion via a P-gp, BCRP or MRP2-dependent mechanism. PBPK illustrates individual contributions of transporters and enzymes to drug disposition as well as their integrated effects [26]

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