Effect of cationic drugs on the transporting activity of human and rat OCT/Oct 1–3 in vitro and implications for drug–drug interactions

Abstract

The inhibitory effects of cationic drugs (β-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 IC₅₀ 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 IC₅₀ 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 IC₅₀ 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.

Keywords::

• hOCT/rOct
• cationic compounds
• inhibition
• drug–drug interaction