Human organic cation transporter 3 mediates the transport of antiarrhythmic drugs.
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.
Hasannejad
Habib
H
Department of Pharmacology and Toxicology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka-shi, Tokyo 181-8611, Japan.
Takeda
Michio
M
Narikawa
Shinichi
S
Huang
Xiu-Lin
XL
Enomoto
Atsushi
A
Taki
Kentarou
K
Niwa
Toshimitsu
T
Jung
Shin Ho
SH
Onozato
Maristela Lika
ML
Tojo
Akihito
A
Endou
Hitoshi
H
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
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