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

• DOI: 10.1007/s11095-022-03171-8
• Publication Date: 2022-01-28T16:02:33Z
• Authors: Eugene C. Chen; Pär Matsson; Mina Azimi; Xujia Zhou; Niklas Handin; Sook Wah Yee; Per Artursson; Kathleen M. Giaco...
• Keywords: Solute carrier family; HEK 293 cells

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