title: The inhibition of human multidrug and toxin extrusion 1 is involved in the drug-drug interaction caused by cimetidine.
abstract: Cimetidine is known to cause drug-drug interactions (DDIs) with organic cations in the kidney, and a previous clinical study showed that coadministration of cimetidine or probenecid with fexofenadine (FEX) decreased its renal clearance. FEX was taken up into human kidney by human organic anion transporter (hOAT) 3 (SLC22A8), but the mechanism of its luminal efflux has not been clarified. The present study examined the molecular mechanism of these DDIs. Saturable uptake of FEX was observed in human kidney slices, with K(m) and V(max) values of 157+/-7 microM and 418+/-16 nmol/15 min/g kidney, respectively. Cimetidine only slightly inhibited its uptake even at 100 microM, far greater than its clinically relevant concentration, whereas 10 microM probenecid markedly inhibited its uptake. As candidate transporters for the luminal efflux of FEX, we focused on human multidrug and toxin extrusions MATE1 (SLC47A1) and MATE2-K (SLC47A2). Saturable uptake of FEX could be observed in human embryonic kidney 293 cells expressing human MATE1 (hMATE1), whereas hMATE2-K-specific uptake of FEX was too small to conduct its further kinetic analysis. The hMATE1-mediated uptake clearance of FEX was inhibited by cimetidine in a concentration-dependent manner, and it was decreased to 60% of the control value in the presence of 3 microM cimetidine. Taken together, our results suggest that the DDI of FEX with probenecid can be explained by the inhibition of renal uptake mediated by hOAT3, whereas the DDI with cimetidine is mainly caused by the inhibition of hMATE1-mediated efflux of FEX rather than the inhibition of its renal uptake process.
authors.affiliation: Department of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Soichiro
authors.initials: S
authors.lastname: Matsushima
authors.forename: Kazuya
authors.initials: K
authors.lastname: Maeda
authors.forename: Katsuhisa
authors.initials: K
authors.lastname: Inoue
authors.forename: Kin-ya
authors.initials: KY
authors.lastname: Ohta
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Yuasa
authors.forename: Tsunenori
authors.initials: T
authors.lastname: Kondo
authors.forename: Hideki
authors.initials: H
authors.lastname: Nakayama
authors.forename: Shigeru
authors.initials: S
authors.lastname: Horita
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kusuhara
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sugiyama
mesh_terms: D002460:Cell Line; D002927:Cimetidine / Q000008:administration & dosage / Q000494:pharmacology*; D004347:Drug Interactions; D006801:Humans; D007668:Kidney / Q000378:metabolism; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors*; D011339:Probenecid / Q000008:administration & dosage / Q000494:pharmacology*; D016593:Terfenadine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D027701:Organic Cation Transport Proteins; C521869:SLC47A1 protein, human; D016593:Terfenadine; D002927:Cimetidine; C093230:fexofenadine; D011339:Probenecid