title: Competitive inhibition of the luminal efflux by multidrug and toxin extrusions, but not basolateral uptake by organic cation transporter 2, is the likely mechanism underlying the pharmacokinetic drug-drug interactions caused by cimetidine in the kidney.
abstract: Cimetidine, an H₂ receptor antagonist, has been used to investigate the tubular secretion of organic cations in human kidney. We report a systematic comprehensive analysis of the inhibition potency of cimetidine for the influx and efflux transporters of organic cations [human organic cation transporter 1 (hOCT1) and hOCT2 and human multidrug and toxin extrusion 1 (hMATE1) and hMATE2-K, respectively]. Inhibition constants (K(i)) of cimetidine were determined by using five substrates [tetraethylammonium (TEA), metformin, 1-methyl-4-phenylpyridinium, 4-(4-(dimethylamino)styryl)-N-methylpyridinium, and m-iodobenzylguanidine]. They were 95 to 146 μM for hOCT2, providing at most 10% inhibition based on its clinically reported plasma unbound concentrations (3.6-7.8 μM). In contrast, cimetidine is a potent inhibitor of MATE1 and MATE2-K with K(i) values (μM) of 1.1 to 3.8 and 2.1 to 6.9, respectively. The same tendency was observed for mouse Oct1 (mOct1), mOct2, and mouse Mate1. Cimetidine showed a negligible effect on the uptake of metformin by mouse kidney slices at 20 μM. Cimetidine was administered to mice by a constant infusion to achieve a plasma unbound concentration of 21.6 μM to examine its effect on the renal disposition of Mate1 probes (metformin, TEA, and cephalexin) in vivo. The kidney- and liver-to-plasma ratios of metformin both were increased 2.4-fold by cimetidine, whereas the renal clearance was not changed. Cimetidine also increased the kidney-to-plasma ratio of TEA and cephalexin 8.0- and 3.3-fold compared with a control and decreased the renal clearance from 49 to 23 and 11 to 6.6 ml/min/kg, respectively. These results suggest that the inhibition of MATEs, but not OCT2, is a likely mechanism underlying the drug-drug interactions with cimetidine in renal elimination.
authors.affiliation: Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Hongo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Sumito
authors.initials: S
authors.lastname: Ito
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kusuhara
authors.forename: Miyu
authors.initials: M
authors.lastname: Yokochi
authors.forename: Junko
authors.initials: J
authors.lastname: Toyoshima
authors.forename: Katsuhisa
authors.initials: K
authors.lastname: Inoue
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Yuasa
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sugiyama
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000378:metabolism; D019797:3-Iodobenzylguanidine / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive / Q000502:physiology; D001692:Biological Transport / Q000187:drug effects; D002506:Cephalexin / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics / Q000652:urine; D002927:Cimetidine / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008687:Metformin / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics / Q000652:urine; D051379:Mice; D008815:Mice, Inbred Strains; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D027702:Organic Cation Transporter 1 / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D000075102:Organic Cation Transporter 2; D011725:Pyridines / Q000378:metabolism; D019789:Tetraethylammonium / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics / Q000652:urine; D014162:Transfection
chemical_list: C442849:4-(4-(dimethylamino)styryl)pyridine; C514424:MATE1 protein, mouse; D027701:Organic Cation Transport Proteins; D027702:Organic Cation Transporter 1; D000075102:Organic Cation Transporter 2; D011725:Pyridines; C491013:SLC22A2 protein, human; C521869:SLC47A1 protein, human; C521870:SLC47A2 protein, human; C491012:Slc22a2 protein, mouse; D019797:3-Iodobenzylguanidine; D019789:Tetraethylammonium; D002927:Cimetidine; D008687:Metformin; D002506:Cephalexin; D015655:1-Methyl-4-phenylpyridinium