title: Liver-selective distribution in rats supports the importance of active uptake into the liver via organic anion transporting polypeptides (OATPs) in humans.
abstract: Organic anion transporting polypeptide (OATP) 1B1 and 1B3 are key molecules that are involved in hepatic uptake related to drug elimination, and OATP-mediated drug interactions are of clinical concern. In this study, with an aim to determine a cutoff value for the potential involvement of OATP, we collected data on the distribution of 12 human OATP and 24 non-OATP radiolabeled substrates in rats. The OATP substrates exhibited a higher tissue-to-plasma ratio (Kp) in the liver than that in the other tissues. As an index of liver-specific distribution, a hepatic Kp ratio (the ratio of Kp in the liver to that in other tissues) was introduced, and a hepatic Kp ratio <10 was proposed as a criterion for excluding the involvement of OATP in vivo. Approximately 20% of the non-OATP substrates as well as 100% of the OATP substrates exceeded the cutoff value of 10; therefore, further in vitro transport studies will be required to decide whether to conduct clinical drug interaction studies. Since distribution studies are usually conducted in rats during drug development, the use of a hepatic Kp ratio is practical and could refine the current decision tree for selecting OATP substrates in the drug interaction guidance/guidelines.
authors.affiliation: Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co, Ltd., Tokyo, Japan. Electronic address: mikkaichi.tsuyoshi.da@daiichisankyo.co.jp.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Mikkaichi
authors.affiliation: Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co, Ltd., Tokyo, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nakai
authors.affiliation: Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co, Ltd., Tokyo, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Yoshigae
authors.affiliation: Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co, Ltd., Tokyo, Japan.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Imaoka
authors.affiliation: Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co, Ltd., Tokyo, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Okudaira
authors.affiliation: Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co, Ltd., Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Izumi
mesh_terms: D000818:Animals; D004347:Drug Interactions; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008970:Molecular Weight; D009928:Organ Specificity; D027361:Organic Anion Transporters / Q000378:metabolism*; D051381:Rats; D014018:Tissue Distribution
chemical_list: D027361:Organic Anion Transporters
keywords: Drug interaction; Hepatic uptake; Organic anion transporting polypeptide; Regulatory science; Tissue distribution