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Organic cation (OC) transporter 2 (OCT2) mediates the first step in the renal secretion of many cationic drugs: basolateral uptake from blood into proximal tubule cells. The impact of this process on the pharmacokinetics of drug clearance as estimated using a physiologically-based pharmacokinetic approach relies on an accurate understanding of the kinetics of transport because the ratio of the maximal rate of transport to the Michaelis constant (i.e., J max / K t ) provides an estimate of the intrinsic clearance (Cl int ) used in in vitro-in vivo extrapolation of experimentally determined transport data. Although the multispecificity of renal OC secretion, including that of the OCT2 transporter, is widely acknowledged, the possible relationship between relative affinity of the transporter for its diverse substrates and the maximal rates of their transport has received little attention. In this study, we determined the J max and apparent Michaelis constant (K tapp ) values for six structurally distinct OCT2 substrates and found a strong correlation between J max and K tapp ; high-affinity substrates [K tapp values &lt;50 µ M, including 1-methyl-4-phenylpyridinium, or 1-methyl-4-phenylpyridinium (MPP), and cimetidine] displayed systematically lower J max values (&lt;50 pmol cm -2 min -1 ) than did low-affinity substrates (K tapp &gt;200 µ M, including choline and metformin). Similarly, preloading OCT2-expressing cells with low-affinity substrates resulted in systematically larger trans -stimulated rates of MPP uptake than did preloading with high-affinity substrates. The data are quantitatively consistent with the hypothesis that dissociation of bound substrate from the transporter is rate limiting in establishing maximal rates of OCT2-mediated transport. This systematic relationship may provide a means to estimate Cl int for drugs for which transport data are lacking.

Correlation between Apparent Substrate Affinity and OCT2 Transport Turnover