title: Human organic cation transporter 3 mediates the transport of antiarrhythmic drugs.
abstract: Antiarrhythmic drugs have been considered to be transported by the organic cation transport system. The purpose of this study was to elucidate the molecular mechanism underlying the transport of antiarrhythmic drugs using cells from the second segment of the proximal tubule (S2) cells of mice expressing human-organic cation transporter 3 (S2 human-OCT3). The antiarrhythmic drugs tested were cibenzoline, disopyramide, lidocaine, mexiletine, phenytoin, pilsicanide, procainamide and quinidine. Human-OCT3 mediated a time- and dose-dependent uptake of quinidine and lidocaine, with Km values of 216 and 139 microM, respectively. Human-OCT3 also mediated the uptake of disopyramide and procainamide but not that of phenytoin. All antiarrhythmic drugs tested inhibited histamine uptake mediated by human-OCT3 in a dose-dependent manner. The IC50 values of antiarrhythmic drugs for human-OCT3 ranged between 0.75 and 656 microM. Kinetic analysis revealed that disopyramide, lidocaine, procainamide and quinidine inhibited histamine uptake mediated by human-OCT3 in a competitive manner. In conclusion, these results suggest that human-OCT3 mediates the transport of antiarrhythmic drugs, which may be the mechanism underlying the distribution and the elimination of these drugs.
authors.affiliation: Department of Pharmacology and Toxicology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka-shi, Tokyo 181-8611, Japan.
authors.forename: Habib
authors.initials: H
authors.lastname: Hasannejad
authors.forename: Michio
authors.initials: M
authors.lastname: Takeda
authors.forename: Shinichi
authors.initials: S
authors.lastname: Narikawa
authors.forename: Xiu-Lin
authors.initials: XL
authors.lastname: Huang
authors.forename: Atsushi
authors.initials: A
authors.lastname: Enomoto
authors.forename: Kentarou
authors.initials: K
authors.lastname: Taki
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Niwa
authors.forename: Shin Ho
authors.initials: SH
authors.lastname: Jung
authors.forename: Maristela Lika
authors.initials: ML
authors.lastname: Onozato
authors.forename: Akihito
authors.initials: A
authors.lastname: Tojo
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Endou
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D004206:Disopyramide / Q000493:pharmacokinetics / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006632:Histamine / Q000493:pharmacokinetics; D006801:Humans; D008012:Lidocaine / Q000493:pharmacokinetics / Q000494:pharmacology; D051379:Mice; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D010672:Phenytoin / Q000493:pharmacokinetics / Q000494:pharmacology; D011342:Procainamide / Q000493:pharmacokinetics / Q000494:pharmacology; D011802:Quinidine / Q000493:pharmacokinetics / Q000494:pharmacology; D000099254:Organic Cation Transporter 3
chemical_list: D000889:Anti-Arrhythmia Agents; D004206:Disopyramide; D006632:Histamine; D008012:Lidocaine; D027701:Organic Cation Transport Proteins; D010672:Phenytoin; D011342:Procainamide; D011802:Quinidine; D000099254:Organic Cation Transporter 3