Abstract
Cytochrome P450 enzymes and human organic anion transporting polypeptide (OATP) 1B1 are reported to be involved in the pharmacokinetics of lobeglitazone (LB), a new peroxisome proliferator–activated receptor γ agonist. Atorvastatin (ATV), a substrate for CYP3A and human OATP1B1, is likely to be coadministered 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 administered intravenously with ATV, the systemic clearance and volume of distribution at steady state for LB remained unchanged (2.67 ± 0.63 ml/min per kg and 289 ± 20 ml/kg, respectively), compared with that of LB without ATV (2.34 ± 0.37 ml/min per kg and 271 ± 20 ml/kg, respectively). Although the tissue-to-plasma partition coefficient (Kp) of LB was not affected by ATV in most major tissues, the liver Kp for LB was decreased by ATV coadministration. Steady-state liver Kp values for three levels of LB were significantly decreased as a result of ATV coadministration. LB uptake was inhibited by ATV in rat OATP1B2-overexpressing Madin–Darby canine kidney cells and in isolated rat hepatocytes in vitro. After incorporating the kinetic parameters for the in vitro studies into a 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 rat OATP1B2, and carrier-mediated transport is involved in the liver-specific drug–drug interaction between LB and ATV in vivo.
Footnotes
- Received November 1, 2016.
- Accepted January 5, 2017.
This research was supported by the National Research Foundation of Korea, funded by the Korean government [Grant 2009-0083533].
A portion of this work was previously presented as a poster Interaction between Lobeglitazone and Atorvastatin in Rats: Potential Involvement of Transporter-Mediated Interaction in the Hepatic Uptake. Yim CS, Jeong YS, Lee SY, Ryu HM, Lee W, Dae-Duk K, Chung SJ: (2016) 11th International Society for the Study of Xenobiotics Meeting; 2016 Jun 12–16; Busan, Republic of Korea.
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- Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics
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