Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California, USA.
Department of Pharmacology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Pharm Res. 2022 Jul;39(7):1599-1613. doi: 10.1007/s11095-022-03171-8. Epub 2022 Jan 28.
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).
The goal of the current study was to identify prescription drug inhibitors of OCT3.
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.
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).
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.
有机阳离子转运体 3（OCT3，SLC22A3）广泛表达，与包括内源性分子、环境毒素和处方药在内的广泛化合物相互作用。作为药代动力学和药效学的决定因素研究不足，OCT3 有可能成为药物吸收和分布的主要决定因素，并成为药物-药物相互作用（DDI）的靶点。
本研究的目的是鉴定 OCT3 的处方药抑制剂。
我们使用稳定表达 OCT3 的 HEK-293 细胞中的高通量测定法筛选了由 2556 种处方药、生物活性分子和天然产物组成的化合物库。
我们鉴定出 210 种化合物，在 20μM 时可抑制 4-Di-1-ASP（2μM）摄取的 50%或更多。其中，有 9 种被预测在临床相关的未结合血浆浓度下抑制转运蛋白。结构-活性关系（SAR）模型包括能够区分 OCT3 抑制剂和非抑制剂的分子描述符，并用于鉴定其他 OCT3 抑制剂。人脑微血管（BMV）的蛋白质组学表明，OCT3 是血脑屏障（BBB）中表达最高的 OCT。
这项研究代表了鉴定 OCT3 处方药抑制剂的最大筛选。其中一些在治疗性未结合血浆水平下对转运体具有足够的抑制作用，可能导致 DDI 或非靶标药理作用。
