Predicting the potential for organic cation transporter 1-mediated drug-drug interactions with fenoterol by amitriptyline, fluoxetine, selegiline, metformin, and verapamil.

Abstract

Background: Despite pharmacogenetic studies with human organic cation transporter (OCT) 1-deficient subjects presenting increased systemic concentrations of OCT1 substrates, highlighting clinical concern for potential drug-drug interactions (DDIs), specifically with the narrow therapeutic index substrate fenoterol, evaluation of new drug entities against OCT1 is not mandated by ICH M12.

Research design and methods: Linear uptake (1 min, 0.831 µM = K_M) of fenoterol was validated in HEK-293 cells overexpressing OCT1 as a prelude to assessing likely comedications (amitriptyline 0.03-30 µM, fluoxetine 0.1-100 µM, selegiline 1-1000 µM, metformin 300-300,000 µM, verapamil 0.06-60 µM) as inhibitors of OCT1. K_i values were integrated into mechanistic static equations to quantify potential DDI with object fenoterol.

Results: Determined K_i values of 0.527 ± 0.276 µM, 5.08 ± 0.907 µM, 13.1 ± 5.73 µM, 7230 ± 1460 µM, and 0.339 ± 0.0994 µM for amitriptyline, fluoxetine, selegiline, metformin, and verapamil, predicted fenoterol AUCRs of 1.09, 1.06, 1.02, 1.02, and 2.11 due to hepatic OCT1 inhibition, respectively.

Conclusions: An in vitro OCT1 inhibition assay using fenoterol as probe substrate was validated and identified that verapamil may pose a clinically relevant interaction risk, predicting a minimum 2-fold increase in fenoterol exposure. This highlights the need for caution when coadministrating verapamil with fenoterol and supports incorporating OCT1 inhibition profiling into preclinical evaluation of new drug entities to better inform clinical development and ensure patient safety.