title: Dehydroepiandrosterone sulfate, a useful endogenous probe for evaluation of drug-drug interaction on hepatic organic anion transporting polypeptide (OATP) in cynomolgus monkeys.
abstract: Since drug-drug interaction (DDI) can affect organic anion-transporting polypeptide (OATP) and cause clinical events, prediction of such DDI is important in early clinical development. Although statins are useful probes for OATP-mediated DDI, endogenous probes would be more practical for predicting such DDI. In this study, we investigate the possible use of dehydroepiandrosterone sulfate (DHEAS), an endogenous OATP substrate, in predicting OATP-mediated DDI in cynomolgus monkeys as a first step toward in human assessment. In in vitro experiments, both human and cynomolgus monkey hepatocytes showed a time- and temperature-dependent DHEAS uptake. Rifampicin (RIF), a typical OATP inhibitor, inhibited this uptake, indicating the involvement of OATP in DHEAS uptake. In in vivo experiments, the area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax) of DHEAS were significantly increased following administration of RIF 10 mg/kg, although the extent of this increase was lower than that observed with the test-statins used in this study. However, based on the results of in vitro hepatic DHEAS uptake, changes in DHEAS concentration are expected to be more prominent in human than in monkey. This shows for the first time that DHEAS may be used as endogenous probe for predicting OATP-mediated DDI.
authors.affiliation: Preclinical Research Laboratories, Sumitomo Dainippon Pharma Co., Ltd., Osaka, Japan; Institute of Medical, Pharmaceutical and Health Sciences, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan. Electronic address: masaki-watanabe@ds-pharma.co.jp.
authors.forename: Masaki
authors.initials: M
authors.lastname: Watanabe
authors.affiliation: Preclinical Research Laboratories, Sumitomo Dainippon Pharma Co., Ltd., Osaka, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Preclinical Research Laboratories, Sumitomo Dainippon Pharma Co., Ltd., Osaka, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Yabuki
authors.affiliation: Institute of Medical, Pharmaceutical and Health Sciences, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan.
authors.forename: Ikumi
authors.initials: I
authors.lastname: Tamai
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019314:Dehydroepiandrosterone Sulfate / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D004347:Drug Interactions; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D008874:Midazolam / Q000493:pharmacokinetics / Q000494:pharmacology*; D027361:Organic Anion Transporters / Q000187:drug effects / Q000378:metabolism*; D012293:Rifampin / Q000494:pharmacology*; D013696:Temperature
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D027361:Organic Anion Transporters; D019314:Dehydroepiandrosterone Sulfate; D008874:Midazolam; D012293:Rifampin
keywords: Cynomolgus monkey; Dehydroepiandrosterone sulfate; Drug–drug interaction; Endogenous probe; Organic anion-transporting polypeptide (OATP); Rifampicin