Mechanistic Evaluation of the Complex Drug-Drug Interactions of Maraviroc: Contribution of Cytochrome P450 3A, P-Glycoprotein and Organic Anion Transporting Polypeptide 1B1

Abstract

The aim of the present study was to quantitatively evaluate the drugdrug interactions (DDIs) of maraviroc (MVC) with various perpetrator drugs, including telaprevir (TVR), using an in vitro data-informed physiologically based pharmacokinetic (PBPK) model. MVC showed significant active uptake and biliary excretion in sandwich-cultured human hepatocytes, and biphasic organic anion transporting polypeptide (OATP)1B1-mediated uptake kinetics in transfected cells (high-affinity K m ∼5 mM). No measureable active uptake was noted in OATP1B3-and OATP2B1-transfceted cells. TVR inhibited OATP1B1-mediated MVC transport in vitro, and also exhibited CYP3A time-dependent inhibition in human hepatocytes (inactivation constant, K I = 2.24 mM, and maximum inactivation rate constant, k inact = 0.0112 minute 21 ). The inactivation efficiency (k inact /K I ) was approximately 34-fold lower in human hepatocytes compared with liver microsomes. A PBPK model accounting for interactions involving CYP3A, P-glycoprotein (P-gp), and OATP1B1 was developed based on in vitro mechanistic data. MVC DDIs with ketoconazole (inhibition of CYP3A and P-gp), ritonavir (inhibition of CYP3A and P-gp), efavirenz (induction of CYP3A), rifampicin (induction of CYP3A and P-gp; inhibition of OATP1B1), and TVR (inhibition of CYP3A, P-gp, and OATP1B1) were well described by the PBPK model with optimized transporter K i values implying that OATP1B1-mediated uptake along with CYP3A metabolism determines the hepatic clearance of MVC, and P-gp-mediated efflux limits its intestinal absorption. In summary, MVC disposition involves intestinal P-gp/CYP3A and hepatic OATP1B1/CYP3A interplay, and TVR simultaneously inhibits these multiple mechanisms leading to a strong DDI-about 9.5fold increase in MVC oral exposure.

The Development and Validation of a Novel “Dual Cocktail” Probe for Cytochrome P450s and Transporter Functions to Evaluate Pharmacokinetic Drug-Drug and Herb-Drug Interactions

“…A single oral dose of ketoconazole increased the plasma concentrations of nifedipine and omeprazole. Based on the inhibitory effect of ketoconazole on CYP3a [ 72 ], a decreased dehydronifedipine formation and an increased nifedipine concentration in rat plasma could be expected, which was consistent with previous reports [ 17 , 18 ]. In case of omeprazole, CYP3A and CYP2C19 are involved in the omeprazole metabolism resulting in the formation of omeprazole sulfone and 5-hydroxyomeprazole, respectively [ 56 ].…”

Beverage–Drug Interaction: Effects of Green Tea Beverage Consumption on Atorvastatin Metabolism and Membrane Transporters in the Small Intestine and Liver of Rats

“…Recently, several studies have demonstrated that the activities of CYP3A, P-gp, and selected OATPs in the intestine and/or liver may be involved in food/beverage–drug interactions [ 8 , 9 , 10 ]. In the intestine and liver, GT extract or EGCG may inhibit both CYP3A activity and P-gp, resulting in increasing intestinal drug absorption and plasma drug concentrations [ 16 , 20 ].…”

“…Recent evidence has suggested that modulations of the activities of CYP3A, P-gp, and OATPs in the intestine or liver may be involved in food/beverage–drug interactions [ 8 , 9 , 10 ]. Studies have indicated that the inhibition of CYP3A or P-gp in the intestine or liver by the consumption of grapefruit juice increases the bioavailability of several orally administered drugs, including lovastatin, simvastatin, and atorvastatin [ 10 , 11 ].…”

A Simple Decision Tree Suited for Identification of Early Oral Drug Candidates With Likely Pharmacokinetic Nonlinearity by Intestinal CYP3A Saturation

“…Maraviroc is reported to be a substrate of organic anion transporting polypeptide (OATP)1B1 with its K m value of 5 mM. 20 After administration of the maraviroc in a Phase 1 study, the C max, bood, u were approximately 1.4 mM even at 1200 mg. In addition, the maximal concentration of unbound maraviroc at the hepatic inlet (C max,in,u ) at 100 and 1200 mg were calculated to be 5.6 and 67.4 mM, respectively.…”