title: Modeling approach for multiple transporters-mediated drug-drug interactions in sandwich-cultured human hepatocytes: effect of cyclosporin A on hepatic disposition of mycophenolic acid phenyl-glucuronide.
abstract: A lower exposure of mycophenolic acid (MPA) in patients receiving MPA-mofetil in combination with cyclosporin A (CsA) is thought to be due to the inhibition of enterohepatic circulation of phenyl-glucuronide of MPA (MPAG). This study aimed to evaluate the interaction of CsA with hepatic disposition of MPA and MPAG in sandwich-cultured human hepatocytes (SCHH) by a mathematical modeling approach. In addition, the inhibition of CsA for glucuronidation of MPA to MPAG was examined in human liver microsomes. Inhibitory parameters of CsA for hepatic disposition of MPAG were estimated using a non-linear mixed effect model program, NONMEM. As a result, CsA did not influence the conversion of MPA to MPAG in either SCHH or human liver microsomes. In contrast, CsA inhibited the basolateral uptake of MPAG with an estimated maximum inhibitory effect (Imax) of 32.4%. CsA also inhibited basolateral efflux and biliary excretion of MPAG formed in SCHH, and the concentration producing 50% of Imax (IC50) for biliary excretion was lower than that for basolateral efflux. Our modeling approach suggests that CsA inhibits both basolateral uptake and biliary excretion of MPAG and leads to changes in systemic exposure of MPA and MPAG in humans.
authors.affiliation: Department of Membrane Transport and Biopharmaceutics, Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan; Pharmacokinetic Research Laboratories, Ono Pharmaceutical Co., Ltd., Tsukuba, Japan.
authors.forename: Norikazu
authors.initials: N
authors.lastname: Matsunaga
authors.affiliation: Pharmacokinetic Research Laboratories, Ono Pharmaceutical Co., Ltd., Tsukuba, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: Department of Membrane Transport and Biopharmaceutics, Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan.
authors.forename: Takeo
authors.initials: T
authors.lastname: Nakanishi
authors.affiliation: Pharmacokinetic Research Laboratories, Ono Pharmaceutical Co., Ltd., Tsukuba, Japan.
authors.forename: Mikio
authors.initials: M
authors.lastname: Ogawa
authors.affiliation: Pharmacokinetic Research Laboratories, Ono Pharmaceutical Co., Ltd., Tsukuba, Japan.
authors.forename: Haruo
authors.initials: H
authors.lastname: Imawaka
authors.affiliation: Department of Membrane Transport and Biopharmaceutics, Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan. Electronic address: tamai@p.kanazawa-u.ac.jp.
authors.forename: Ikumi
authors.initials: I
authors.lastname: Tamai
mesh_terms: D001692:Biological Transport; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004764:Enterohepatic Circulation; D020719:Glucuronides / Q000378:metabolism*; D065669:Hepatobiliary Elimination / Q000187:drug effects; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D049990:Membrane Transport Modulators / Q000494:pharmacology*; D026901:Membrane Transport Proteins / Q000187:drug effects* / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism; D008954:Models, Biological; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D020719:Glucuronides; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins; C113145:mycophenolic acid glucuronide; D016572:Cyclosporine; D009173:Mycophenolic Acid
keywords: Drug transporter; Drug–drug interaction; Hepatic disposition; Mathematical modeling; Sandwich-cultured human hepatocytes