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

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 H₂-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 [³H]-MPP and [¹⁴C]-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 [³H]-MPP and [¹⁴C]-TEA uptake by hOCT1-3/rOct1-3 were lower than that for metformin. The [³H]-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.