title: Specific Inhibition of the Distribution of Lobeglitazone to the Liver by Atorvastatin in Rats: Evidence for a Rat Organic Anion Transporting Polypeptide 1B2-Mediated Interaction in Hepatic Transport.
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 Kpfor LB was decreased by ATV coadministration. Steady-state liver Kpvalues 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.
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Gwanak-gu, Seoul, Republic of Korea (C.-S.Y., Y.-S.J., S.-Y.L., W.P., H.-M.R., S.-J.C.); Korea Institute of Toxicology, Yuseong-gu, Daejeon, Republic of Korea (J.-H.L.); Life Science Research Center, Daewoong Pharmaceutical Company Ltd., Yongin-si, Gyeonggi-do, Republic of Korea (K.-R.L.); and College of Pharmacy, Gachon University, Yeonsu-gu, Incheon, Republic of Korea (H.-J.M.).
authors.forename: Chang-Soon
authors.initials: CS
authors.lastname: Yim
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Gwanak-gu, Seoul, Republic of Korea (C.-S.Y., Y.-S.J., S.-Y.L., W.P., H.-M.R., S.-J.C.); Korea Institute of Toxicology, Yuseong-gu, Daejeon, Republic of Korea (J.-H.L.); Life Science Research Center, Daewoong Pharmaceutical Company Ltd., Yongin-si, Gyeonggi-do, Republic of Korea (K.-R.L.); and College of Pharmacy, Gachon University, Yeonsu-gu, Incheon, Republic of Korea (H.-J.M.).
authors.forename: Yoo-Seong
authors.initials: YS
authors.lastname: Jeong
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Gwanak-gu, Seoul, Republic of Korea (C.-S.Y., Y.-S.J., S.-Y.L., W.P., H.-M.R., S.-J.C.); Korea Institute of Toxicology, Yuseong-gu, Daejeon, Republic of Korea (J.-H.L.); Life Science Research Center, Daewoong Pharmaceutical Company Ltd., Yongin-si, Gyeonggi-do, Republic of Korea (K.-R.L.); and College of Pharmacy, Gachon University, Yeonsu-gu, Incheon, Republic of Korea (H.-J.M.).
authors.forename: Song-Yi
authors.initials: SY
authors.lastname: Lee
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Gwanak-gu, Seoul, Republic of Korea (C.-S.Y., Y.-S.J., S.-Y.L., W.P., H.-M.R., S.-J.C.); Korea Institute of Toxicology, Yuseong-gu, Daejeon, Republic of Korea (J.-H.L.); Life Science Research Center, Daewoong Pharmaceutical Company Ltd., Yongin-si, Gyeonggi-do, Republic of Korea (K.-R.L.); and College of Pharmacy, Gachon University, Yeonsu-gu, Incheon, Republic of Korea (H.-J.M.).
authors.forename: Wonji
authors.initials: W
authors.lastname: Pyeon
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Gwanak-gu, Seoul, Republic of Korea (C.-S.Y., Y.-S.J., S.-Y.L., W.P., H.-M.R., S.-J.C.); Korea Institute of Toxicology, Yuseong-gu, Daejeon, Republic of Korea (J.-H.L.); Life Science Research Center, Daewoong Pharmaceutical Company Ltd., Yongin-si, Gyeonggi-do, Republic of Korea (K.-R.L.); and College of Pharmacy, Gachon University, Yeonsu-gu, Incheon, Republic of Korea (H.-J.M.).
authors.forename: Heon-Min
authors.initials: HM
authors.lastname: Ryu
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Gwanak-gu, Seoul, Republic of Korea (C.-S.Y., Y.-S.J., S.-Y.L., W.P., H.-M.R., S.-J.C.); Korea Institute of Toxicology, Yuseong-gu, Daejeon, Republic of Korea (J.-H.L.); Life Science Research Center, Daewoong Pharmaceutical Company Ltd., Yongin-si, Gyeonggi-do, Republic of Korea (K.-R.L.); and College of Pharmacy, Gachon University, Yeonsu-gu, Incheon, Republic of Korea (H.-J.M.).
authors.forename: Jong-Hwa
authors.initials: JH
authors.lastname: Lee
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Gwanak-gu, Seoul, Republic of Korea (C.-S.Y., Y.-S.J., S.-Y.L., W.P., H.-M.R., S.-J.C.); Korea Institute of Toxicology, Yuseong-gu, Daejeon, Republic of Korea (J.-H.L.); Life Science Research Center, Daewoong Pharmaceutical Company Ltd., Yongin-si, Gyeonggi-do, Republic of Korea (K.-R.L.); and College of Pharmacy, Gachon University, Yeonsu-gu, Incheon, Republic of Korea (H.-J.M.).
authors.forename: Kyeong-Ryoon
authors.initials: KR
authors.lastname: Lee
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Gwanak-gu, Seoul, Republic of Korea (C.-S.Y., Y.-S.J., S.-Y.L., W.P., H.-M.R., S.-J.C.); Korea Institute of Toxicology, Yuseong-gu, Daejeon, Republic of Korea (J.-H.L.); Life Science Research Center, Daewoong Pharmaceutical Company Ltd., Yongin-si, Gyeonggi-do, Republic of Korea (K.-R.L.); and College of Pharmacy, Gachon University, Yeonsu-gu, Incheon, Republic of Korea (H.-J.M.).
authors.forename: Han-Joo
authors.initials: HJ
authors.lastname: Maeng
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Gwanak-gu, Seoul, Republic of Korea (C.-S.Y., Y.-S.J., S.-Y.L., W.P., H.-M.R., S.-J.C.); Korea Institute of Toxicology, Yuseong-gu, Daejeon, Republic of Korea (J.-H.L.); Life Science Research Center, Daewoong Pharmaceutical Company Ltd., Yongin-si, Gyeonggi-do, Republic of Korea (K.-R.L.); and College of Pharmacy, Gachon University, Yeonsu-gu, Incheon, Republic of Korea (H.-J.M.) sukjae@snu.ac.kr.
authors.forename: Suk-Jae
authors.initials: SJ
authors.lastname: Chung
mesh_terms: D000818:Animals; D000069059:Atorvastatin / Q000097:blood / Q000494:pharmacology*; D001692:Biological Transport; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D007275:Injections, Intravenous; D008099:Liver / Q000378:metabolism*; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D008657:Metabolic Clearance Rate; D008862:Microsomes, Liver / Q000378:metabolism; D008954:Models, Biological; D011743:Pyrimidines / Q000097:blood / Q000493:pharmacokinetics*; D017207:Rats, Sprague-Dawley; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3 / Q000235:genetics / Q000378:metabolism*; D013379:Substrate Specificity; D045162:Thiazolidinediones / Q000097:blood / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D014162:Transfection
chemical_list: D011743:Pyrimidines; C421207:Slco1b2 protein, rat; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D045162:Thiazolidinediones; D000069059:Atorvastatin; C546215:lobeglitazone