Kinetic and selectivity differences between rodent, rabbit, and human organic cation transporters (OCT1)

Organic cation transporters play an important role in the absorption, distr ibution, and elimination of clinical agents, toxic substances, and endogeno us compounds. In kidney preparations, significant differences in functional characteristics of organic cation transport between various species have b een reported. However, the underlying molecular mechanisms responsible for these interspecies differences are not known. The goal of this study was to determine the kinetics and substrate selectivities of organic cation trans porter (OCT1) homologs from mouse, rat, rabbit, and human that may contribu te to interspecies differences in the renal and hepatic handling of organic cations. With a series of n-tetraalkylammonium (nTAA) compounds, a correla tion between increasing alkyl chain length and affinity for the four OCT1 h omologs was observed. However, the apparent affinity constants (K-i) differ ed among the species homologs. For the mouse homolog mOCT1, apparent K-i va lues ranged from 7 mu M for tetrabutylammonium to 2000 mM for tetramethylam monium. In contrast, the human homolog hOCT1 exhibited weaker interactions with the nTAA compounds. Trans-stimulation studies and current measurements in voltage-clamped oocytes demonstrated that larger nTAA compounds were tr ansported at greater rates in oocytes expressing hOCT1, whereas smaller nTA As were transported at greater rates in oocytes expressing mOCT1 or rOCT1. The rabbit homolog rbOCT1 exhibited intermediate properties in its interact ions with nTAAs compared with its rodent and human counterparts. This repor t demonstrates that the human OCT1 homolog has functional properties distin ct from those of the rodent and rabbit OCT1 homologs. The study underscores potential difficulties in extrapolating data from preclinical studies in a nimal models to humans.