title: Quantitative Analyses of Hepatic OATP-Mediated Interactions Between Statins and Inhibitors Using PBPK Modeling With a Parameter Optimization Method.
abstract: This study aimed to construct a widely applicable method for quantitative analyses of drug-drug interactions (DDIs) caused by the inhibition of hepatic organic anion transporting polypeptides (OATPs) using physiologically based pharmacokinetic (PBPK) modeling. Models were constructed for pitavastatin, fluvastatin, and pravastatin as substrates and cyclosporin A (CsA) and rifampicin (RIF) as inhibitors, where enterohepatic circulations (EHC) of statins were incorporated. By fitting to clinical data, parameters that described absorption, hepatic elimination, and EHC processes were optimized, and the extent of these DDIs was explained satisfactorily. Similar in vivo inhibition constant (Ki) values of each inhibitor against OATPs were obtained, regardless of the substrates. Estimated Kivalues of CsA were comparable to reported in vitro values with the preincubation of CsA, while those of RIF were smaller than reported in vitro values (coincubation). In conclusion, this study proposes a method to optimize in vivo PBPK parameters in hepatic uptake transporter-mediated DDIs.
authors.affiliation: Sugiyama Laboratory, RIKEN Innovation Center, RIKEN, Yokohama, Kanagawa, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Yoshikado
authors.affiliation: Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: Clinical Pharmacology Strategy Group, Translational Clinical Research Science & Strategy Dept., Chugai Pharmaceutical Co., Tokyo, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Kotani
authors.affiliation: DMPK Research Laboratories Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma, Chiba, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Nakada
authors.affiliation: Pharmacokinetic Research Laboratories, Ono Pharmaceutical Co., Ibaraki, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Asaumi
authors.affiliation: Sugiyama Laboratory, RIKEN Innovation Center, RIKEN, Yokohama, Kanagawa, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Toshimoto
authors.affiliation: Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Maeda
authors.affiliation: Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Kusuhara
authors.affiliation: Sugiyama Laboratory, RIKEN Innovation Center, RIKEN, Yokohama, Kanagawa, Japan. ychi.sugiyama@riken.jp.
authors.forename: Y
authors.initials: Y
authors.lastname: Sugiyama
mesh_terms: D000904:Antibiotics, Antitubercular / Q000494:pharmacology; D003198:Computer Simulation; D016572:Cyclosporine / Q000494:pharmacology; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005229:Fatty Acids, Monounsaturated / Q000097:blood / Q000493:pharmacokinetics; D000077340:Fluvastatin; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D007211:Indoles / Q000097:blood / Q000493:pharmacokinetics; D008099:Liver / Q000378:metabolism*; D008954:Models, Biological; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D017035:Pravastatin / Q000097:blood / Q000493:pharmacokinetics; D011804:Quinolines / Q000097:blood / Q000493:pharmacokinetics; D012293:Rifampin / Q000494:pharmacology
chemical_list: D000904:Antibiotics, Antitubercular; D004791:Enzyme Inhibitors; D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D027361:Organic Anion Transporters; D011804:Quinolines; D000077340:Fluvastatin; D016572:Cyclosporine; D017035:Pravastatin; C108475:pitavastatin; D012293:Rifampin