RT Journal Article
SR Electronic
T1 Specific Inhibition of the Distribution of Lobeglitazone to the Liver by Atorvastatin in Rats: Evidence for an rOATP1B2-Mediated Interaction in Hepatic Transport
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.116.074120
DO 10.1124/dmd.116.074120
A1 Chang-Soon Yim
A1 Yoo-Seong Jeong
A1 Song-Yi Lee
A1 Wonji Pyeon
A1 Heon-Min Ryu
A1 Jong-Hwa Lee
A1 Kyeong-Ryoon Lee
A1 Han-Joo Maeng
A1 Suk-Jae Chung
YR 2017
UL http://dmd.aspetjournals.org/content/early/2017/01/09/dmd.116.074120.abstract
AB 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.