title: Interaction and transport characteristics of mycophenolic acid and its glucuronide via human organic anion transporters hOAT1 and hOAT3.
abstract: The immunosuppressant mycophenolate mofetil (MMF) is frequently administered with calcineurin inhibitors and corticosteroids to recipients of organ transplantations. However, the renal handling of the active metabolite mycophenolic acid (MPA) and 7-O-MPA-glucuronide (MPAG) has been unclear. The purpose of the present study was to assess the interaction of MPA and MPAG with the human renal organic anion transporters hOAT1 (SLC22A6) and hOAT3 (SLC22A8), by conducting uptake experiments using HEK293 cells stably expressing these transporters. MPA and MPAG inhibited the time-dependent uptake of p-[(14)C]aminohippurate by hOAT1 and that of [(3)H]estrone sulfate by hOAT3. The apparent 50% inhibitory concentration (IC(50)) of MPA for hOAT1 and hOAT3 was estimated at 10.7 and 1.5 microM, respectively. In the case of MPAG, the IC(50) values were calculated at 512.3 microM for hOAT1 and 69.1 microM for hOAT3. Eadie-Hofstee plot analyses showed that they inhibited hOAT1 noncompetitively and hOAT3 competitively. No inhibitory effects of tacrolimus, cyclosporin A and azathioprine on transport of p-[(14)C]aminohippurate by hOAT1 and of [(3)H]estrone sulfate by hOAT3 were observed. No transport of MPA by these transporters was observed. On the other hand, the uptake of MPAG into cells was stimulated by the expression of hOAT3, but not hOAT1. These findings propose the possibility that the administration of MMF decreases the renal clearance of drugs which are substrates of hOAT1 and hOAT3. Present data suggest that hOAT3 contributes to the renal tubular secretion of MPAG.
authors.affiliation: Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Uwai
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Motohashi
authors.forename: Yoshie
authors.initials: Y
authors.lastname: Tsuji
authors.forename: Harumasa
authors.initials: H
authors.lastname: Ueo
authors.forename: Toshiya
authors.initials: T
authors.lastname: Katsura
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Inui
mesh_terms: D001692:Biological Transport / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D020719:Glucuronides / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007166:Immunosuppressive Agents / Q000378:metabolism / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D027362:Organic Anion Transport Protein 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D029362:Organic Anion Transporters, Sodium-Independent / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013997:Time Factors
chemical_list: D004791:Enzyme Inhibitors; D020719:Glucuronides; D007166:Immunosuppressive Agents; D027362:Organic Anion Transport Protein 1; D029362:Organic Anion Transporters, Sodium-Independent; C114338:organic anion transport protein 3; C113145:mycophenolic acid glucuronide; D009173:Mycophenolic Acid