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

Sook Wah Yee,Mina Azimi,Pär Matsson,Niklas Handin,Kathleen M. Giacomini,Xujia Zhou,Per Artursson,Eugene C. Chen

doi:10.1007/s11095-022-03171-8

Abstract

IntroductionThe 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).GoalThe goal of the current study was to identify prescription drug inhibitors of OCT3.MethodsWe 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.ResultsWe 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).ConclusionsThis 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.

Highlights

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
Our results suggest that the transporter interacts with many prescription drugs, most of which were not previously known to interact with OCT3
Further we determined that OCT3 is the most highly expressed OCT at the human blood-brain barrier (BBB) which suggests that the transporter may be involved in the entry of a diverse array of substrates into the central nervous system (CNS)

Summary

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. Like its paralogs OCT1 and OCT2, OCT3 interacts with a wide array of endogenous and exogenous small organic cations, including vitamins, neurotransmitters, environmental chemicals and prescription drugs [1–3]. Expressed in many tissues including placenta, heart, lung, liver, intestine, prostate, skeletal muscle, and brain and diverse substrates, OCT3 is involved in many pleiotropic effects. Human genetic studies have revealed important roles of OCT3 in metabolic and cardiac effects. Human genetic studies reveal roles of OCT3 in cardiac pathologies including coronary artery disease, myocardial infarction, and ischemic stroke [7–10]. Deficiency in the serotonin (5-HT) transporter, SERT, linked to mood disorders and depression, has been shown to be compensated for by increased OCT3 levels in the brains of mice [13]. Mutations in OCT3 have been linked to children with obsessive compulsive disorder [16]

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