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Tricyclic antidepressants as inhibitors of the multidrug transporter, human OCT2: Influence of structural similarity to inhibitory efficacy

Organic cation transporter 2 (OCT2) mediates the initial step in renal secretion of organic cations, which comprise approximately 40% of currently prescribed drugs. Due to its potential as a target for unwanted drug‐drug interactions (DDIs), much attention has been directed toward understanding the basis of OCT2 selectivity. These studies typically assess selectivity based on inhibition profiles for OCT2‐mediated transport of a probe substrate produced by a structurally diverse range of test inhibitors. Here we assessed the profile of OCT2 inhibition produced by 9 structurally similar inhibitors, i.e., a set of tricyclic antidepressants (TCAs). Structural similarity was assessed by Tanimoto coefficients, which ranged from 0.5 to 0.83. As the measure of transport activity we determined uptake of a fluorescent substrate, N,N,N‐trimethyl‐2‐[methyl(7‐nitrobenzo[c][l,2,5]oxadiazol‐4‐yl)amino]ethanaminium iodide (NBD‐MTMA) into cells stably expressing OCT2. Uptake was effectively linear for 5 min, and the Jmax and apparent Kt values for NBD‐MTMA were 25 ± 5.2 pmol cm−2 min−1, and 11.7 ± 5.7 μM, respectively. Despite the structural similarity of the test inhibitors, IC50 values varied by up to 100 fold, from as low as 0.2 ± 0.02 to 0.4 ± 0.03 μM (Amitriptyline and Doxepin), to 2.1 ± 0.07 to 3.1 ± 0.05 μM (for Imipramine and Protriptyline), to as large as 20.2 ± 4.14 to 27.7 ± 1.8 μM (for Chlorpromazine and Butriptyline). There was no correlation between degree of similarity (based on Tanimoto coefficients) and pairwise comparison of IC50 values for all the TCAs tested. The comparatively high affinity of OCT2 for Amitriptyline and Doxepin, combined with reported unbound Cmax levels, resulted in Cmaxub/IC50 ratios that exceed 0.1, highlighting them as potential perpetrators of unwanted DDIs. These data show that similarity of structure is not a good criterion for predicting inhibitory interaction with OCT2.