Effect of cationic drugs on the transporting activity of human and rat OCT/Oct 1-3 in vitro and implications for drug-drug interactions.
The inhibitory effects of cationic drugs (beta-adrenoreceptor antagonists, calcium (Ca)-channel blocker, I(f) channel inhibitor, antiarrhythmic drugs, and antibacterial drugs) that inhibit 1-methyl-4-phenylpyridinium (MPP) and/or metformin uptake into hOCT1-3/rOct1-3-expressing cells and human/rat hepatocytes were investigated in this study. The drug-drug interaction (DDI) potential of these drugs for the hOCT/rOct-mediated hepatic/renal uptake process was also assessed. The IC(50) values of cardiovascular drugs, including an I(f) channel inhibitor with a new mechanism of action, were greater for hOCT2/rOct2 than those for hOCT1/rOct1 or hOCT3/rOct3. No species differences in these values were observed between hOCTs and rOcts. As for hOCT2-mediated uptake, the IC(50) values of quinidine and the I(f) channel inhibitor for metformin uptake were lower than those for MPP uptake. However, previous clinical studies found that the IC(50) values of these drugs for hOCT1/rOct1 and hOCT2/rOct2 were much greater than their unbound plasma concentrations, which suggests that the DDIs of these cationic compounds may not be related to hOCT/rOct-mediated hepatic/renal uptake pathways. In addition, investigation of the luminal transporters of cationic compounds in the kidney, as well as the in vitro DDI potential of their inhibitors, is important for the clarification of cationic compound DDIs in humans.
Umehara
K-I
KI
Drug Metabolism Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., Tokyo, Japan. kenichi.umehara@jp.astellas.com
Iwatsubo
T
T
Noguchi
K
K
Usui
T
T
Kamimura
H
H
D015655:1-Methyl-4-phenylpyridinium / Q000378:metabolism; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology*; D002412:Cations / Q000494:pharmacology*; D002460:Cell Line; D002927:Cimetidine / Q000494:pharmacology; D004347:Drug Interactions; D006635:Histamine H2 Antagonists / Q000494:pharmacology; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology*; D008012:Lidocaine / Q000494:pharmacology; D008687:Metformin / Q000378:metabolism; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000378:metabolism; D011342:Procainamide / Q000494:pharmacology; D011802:Quinidine / Q000494:pharmacology; D051381:Rats
D000889:Anti-Arrhythmia Agents; D000900:Anti-Bacterial Agents; D001549:Benzamides; D002412:Cations; D006635:Histamine H2 Antagonists; D007546:Isoquinolines; D027701:Organic Cation Transport Proteins; C530155:YM 758; D002927:Cimetidine; D008687:Metformin; D008012:Lidocaine; D011802:Quinidine; D011342:Procainamide; D015655:1-Methyl-4-phenylpyridinium