title: Comparison of the kinetic characteristics of inhibitory effects exerted by biguanides and H2-blockers on human and rat organic cation transporter-mediated transport: Insight into the development of drug candidates.
abstract: In this study, the comparison of the transport of substrates (1-methyl-4-phenylpydinium (MPP) and tetraethyl ammonium (TEA)) and the inhibition potency of the inhibitors (biguanides and H(2)-blockers) for human and rat organic cation transporters (hOCTs and rOcts), and the inhibition type of inhibitors for these transporters were investigated using HEK293 cells that stably express hOCT/rOct. The concentration-dependent uptake of [(3)H]-MPP and [(14)C]-TEA by hOCT1-3/rOct1-3 had K(m) values similar to those in the literature. It was also deduced that MPP and TEA are competitive inhibitors for hOCT1-2/rOct1-2. The K(i) values for phenformin inhibition of [(3)H]-MPP and [(14)C]-TEA uptake by hOCT1-3/rOct1-3 were lower than that for metformin. The [(3)H]-MPP uptake by hOCT1/rOct1 and hOCT3/rOct3 was inhibited by famotidine and ranitidine whereas that by hOCT2/rOct2 was not. The inhibitory potency of cimetidine for hOCT1-2 was very weak. In most cases, the differences in the V(max)/K(m) values of substrates and the K(i) values of inhibitors between hOCT and rOct were minor. The acquisition of information on OCT/Oct mediated-transport and/or inhibition such as that presented in this report is very useful for further understanding of certain aspects of uptake, distribution, and excretion for drug candidates.
authors.affiliation: Drug Metabolism Research Laboratories, Drug Discovery Research, Azusawa, Tokyo, Japan.
authors.forename: K-I
authors.initials: KI
authors.lastname: Umehara
authors.forename: T
authors.initials: T
authors.lastname: Iwatsubo
authors.forename: K
authors.initials: K
authors.lastname: Noguchi
authors.forename: H
authors.initials: H
authors.lastname: Kamimura
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000378:metabolism; D000818:Animals; D001645:Biguanides / Q000494:pharmacology*; D002460:Cell Line; D002927:Cimetidine / Q000494:pharmacology; D015195:Drug Design; D015738:Famotidine / Q000494:pharmacology; D006635:Histamine H2 Antagonists / Q000494:pharmacology*; D006801:Humans; D017136:Ion Transport / Q000187:drug effects; D007700:Kinetics; D008687:Metformin / Q000494:pharmacology; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors*; D010629:Phenformin / Q000494:pharmacology; D011899:Ranitidine / Q000494:pharmacology; D051381:Rats; D019789:Tetraethylammonium / Q000378:metabolism
chemical_list: D001645:Biguanides; D006635:Histamine H2 Antagonists; D027701:Organic Cation Transport Proteins; D015738:Famotidine; D019789:Tetraethylammonium; D002927:Cimetidine; D011899:Ranitidine; D008687:Metformin; D010629:Phenformin; D015655:1-Methyl-4-phenylpyridinium