Specific Inhibition of the Distribution of Lobeglitazone to the Liver by Atorvastatin in Rats: Evidence for an rOATP1B2-Mediated Interaction in Hepatic Transport

Abstract

CYP (cytochrome P450) enzymes and hOATP1B1 (organic anion transporting polypeptide 1B1) are reported to be involved in the pharmacokinetics of lobeglitazone (LB), a new PPARγ agonist. Atorvastatin (ATV), a substrate for CYP3A and hOATP1B1, is likely to be co-administered with LB in patients with the metabolic syndrome. We report herein on a study of potential interactions between LB and ATV in rats. When LB was IV (intravenous)-administered with ATV, the systemic clearance (CL

2.67 ± 0.63 mL/min/kg) and volume of distribution at steady-state (Vss

289 ± 20 mL/kg) for LB remained unchanged, compared to those of LB without ATV (CL, 2.34 ± 0.37 mL/min/kg

Vss, 271 ± 20 mL/kg). While the Kp of LB was not affected by ATV in most major tissues, the liver Kp for LB was decreased by the co-administration of ATV. The liver Kp values at the steady state for three levels of LB were significantly decreased as the result of the co-administration of ATV. LB uptake was inhibited by ATV in rOATP1B2-overexpressing MDCK (Madin–Darby canine kidney) cells and in isolated rat hepatocytes in vitro. After incorporating the kinetic parameters for the in vitro studies into a PBPK (physiologically based pharmacokinetics) model, the characteristics of LB distribution to the liver were consistent with the findings of the in vivo study. It thus appears that the distribution of LB to the liver is mediated by the hepatic uptake of transporters such as rOATP1B2, and the carrier-mediated transport is involved in the liver specific DDI (drug-drug interaction) between LB and ATV in vivo.