CYP enzymes and hOATP1B1 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-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 cells and in isolated rat hepatocytes in vitro. After incorporating the kinetic parameters for the in vitro studies into a PBPK 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 between LB and ATV in vivo.
- drug-drug interactions
- in vitro-in vivo prediction (IVIVE)
- modeling and simulation
- physiologically-based pharmacokinetic modeling/PBPK
- Transporter-mediated drug/metabolite disposition
- Uptake transporters (OATP, OAT, OCT, PEPT, MCT, NTCP, ASBT, etc.)
- The American Society for Pharmacology and Experimental Therapeutics