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Introduction The organic cation transporter 3 (OCT3, SLC22A3) is ubiquitously expressed and interacts with a wide array of compounds including endogenous molecules, environmental toxins and prescription drugs. Understudied as a determinant of pharmacokinetics and pharmacodynamics, OCT3 has the potential to be a major determinant of drug absorption and disposition and to be a target for drug-drug interactions (DDIs). Goal The goal of the current study was to identify prescription drug inhibitors of OCT3. Methods We screened a compound library consisting of 2556 prescription drugs, bioactive molecules, and natural products using a high throughput assay in HEK-293 cells stably expressing OCT3. Results We identified 210 compounds that at 20 μM inhibit 50% or more of OCT3-mediated uptake of 4-Di-1-ASP (2 μM). Of these, nine were predicted to inhibit the transporter at clinically relevant unbound plasma concentrations. A Structure-Activity Relationship (SAR) model included molecular descriptors that could discriminate between inhibitors and non-inhibitors of OCT3 and was used to identify additional OCT3 inhibitors. Proteomics of human brain microvessels (BMVs) indicated that OCT3 is the highest expressed OCT in the human blood-brain barrier (BBB). Conclusions This study represents the largest screen to identify prescription drug inhibitors of OCT3. Several are sufficiently potent to inhibit the transporter at therapeutic unbound plasma levels, potentially leading to DDIs or off-target pharmacologic effects.

High Throughput Screening of a Prescription Drug Library for Inhibitors of Organic Cation Transporter 3, OCT3