title: Integrated approach of in vivo and in vitro evaluation of the involvement of hepatic uptake organic anion transporters in the drug disposition in rats using rifampicin as an inhibitor.
abstract: Cumulative studies describe the importance of drug transporters as one of the key determinants of pharmacokinetics that necessitate investigation and assessment of the involvement of drug transporters in drug discovery and development. The present study investigated an integrated in vivo and in vitro approach to determine the involvement of organic anion transporting polypeptides (Oatps) in the disposition of drugs in rats using rifampicin as an inhibitor. When bromosulfophthalein (BSP) and HMG-CoA reductase inhibitors (statins), which were used as model substrates for Oatps, were administered intravenously (3 and 1 mg/kg, respectively) to rats pretreated with rifampicin orally (30 mg/kg), the total plasma clearance of BSP and statins was attenuated compared with that in control rats, suggesting the involvement of Oatps in the disposition of these drugs in vivo. On the other hand, the pharmacokinetics of midazolam, used as a model substrate of cytochrome P450 3a (Cyp3a), was unchanged between control rats and rifampicin-pretreated rats. The involvement of Oatps in the disposition of statins observed in vivo was further clarified by employing an in vitro hepatic uptake study and media-loss assay in the presence or absence of 100 μM rifampicin. Hepatic intrinsic clearance was reduced in the presence of rifampicin in both the media-loss assay and hepatocyte uptake study. The present study suggests in vivo investigations in rats using rifampicin together with in vitro investigations with a media-loss assay and/or uptake assay using rat hepatocytes can help determine whether a clinical drug-drug interaction study is necessary in drug development.
authors: Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. imaoka.tomoki.hd@daiichisankyo.co.jp
authors: Tomoki
authors: T
authors: Imaoka
authors: Tsuyoshi
authors: T
authors: Mikkaichi
authors: Koji
authors: K
authors: Abe
authors: Masakazu
authors: M
authors: Hirouchi
authors: Noriko
authors: N
authors: Okudaira
authors: Takashi
authors: T
authors: Izumi
mesh_terms: D000818:Animals; D004347:Drug Interactions; D005260:Female; D022781:Hepatocytes / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000493:pharmacokinetics; D008099:Liver / Q000378:metabolism*; D008657:Metabolic Clearance Rate; D008874:Midazolam / Q000493:pharmacokinetics; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012293:Rifampin / Q000494:pharmacology*; D013448:Sulfobromophthalein / Q000493:pharmacokinetics
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D027361:Organic Anion Transporters; D013448:Sulfobromophthalein; D008874:Midazolam; D012293:Rifampin