Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.
University of Tuebingen, Tuebingen, Germany.
Br J Pharmacol. 2021 Mar;178(6):1459-1474. doi: 10.1111/bph.15370. Epub 2021 Feb 23.
The metabolic activity of cytochrome P450 (CYP) 2D6 is highly variable and CYP2D6 genotypes insufficiently explain the extensive and intermediate metabolic phenotypes, limiting the prediction of drug response plus adverse drug reactions. Since CYP2D6 prototypic substrates are positively charged, the aim of this study was to evaluate the organic cation transporters (OCTs) and multidrug and toxin extrusion proteins (MATEs) as potential contributors to the variability of CYP2D6 hydroxylation of debrisoquine, dextromethorphan, diphenhydramine, perhexiline and sparteine.
OCT1/SLC22A1-, OCT2/SLC22A2-, OCT3/SLC22A3-, MATE1/SLC47A1-, and MATE2K/SLC47A2-overexpressing cell lines were used to investigate the transport of the selected drugs. Individuals from a study cohort, well defined with respect to CYP2D6 genotype and sparteine pharmacokinetics, were genotyped for the common OCT1 variants rs12208357 (OCT1-R61C), rs34130495 (OCT1-G401S), rs202220802 (OCT1-Met420del), rs34059508 (OCT1-G465R), OCT2 variant rs316019 (OCT2-A270S) and MATE1 variant rs2289669. Sparteine pharmacokinetics was stratified according to CYP2D6 and OCT1, OCT2 or MATE1 genotype.
OCTs and MATE1 transport sparteine and debrisoquine with high affinity in vitro, but OCT- and MATE1-dependent transport of dextromethorphan, diphenhydramine and perhexiline was not detected. Sparteine and debrisoquine transport depends on OCT1 genotype; however, sparteine pharmacokinetics is independent from OCT1 genotype.
Some drugs that are substrates of CYP2D6 are also substrates of OCTs and MATE1, suggesting overlapping specificities. Variability in sparteine hydroxylation in extensive and intermediate metabolizers cannot be explained by OCT1 genetic variants indicating presence of other factors. Dose-dependent toxicities of dextromethorphan, diphenhydramine and perhexiline appear to be independent from OCTs and MATEs.
细胞色素 P450（CYP）2D6 的代谢活性变化很大，CYP2D6 基因型不足以解释广泛和中间代谢表型，限制了药物反应和不良反应的预测。由于 CYP2D6 原型底物带正电荷，本研究旨在评估有机阳离子转运体（OCT）和多药和毒素外排蛋白（MATE）是否可能是 CYP2D6 羟化右美沙芬、右苯氧胺、苯海拉明、哌泊噻嗪和斯帕嗪的变异性的潜在贡献者。
使用 OCT1/SLC22A1-、OCT2/SLC22A2-、OCT3/SLC22A3-、MATE1/SLC47A1-和 MATE2K/SLC47A2 过表达细胞系来研究所选药物的转运。从一项研究队列中选择个体，根据 CYP2D6 基因型和斯帕嗪药代动力学进行明确分类，并对常见的 OCT1 变体 rs12208357（OCT1-R61C）、rs34130495（OCT1-G401S）、rs202220802（OCT1-Met420del）、rs34059508（OCT1-G465R）、OCT2 变体 rs316019（OCT2-A270S）和 MATE1 变体 rs2289669 进行基因分型。根据 CYP2D6 和 OCT1、OCT2 或 MATE1 基因型对斯帕嗪药代动力学进行分层。
OCTs 和 MATE1 在体外以高亲和力转运斯帕嗪和地昔帕明，但未检测到去甲右苯氧胺、苯海拉明和哌泊噻嗪的 OCT 和 MATE 依赖性转运。斯帕嗪和地昔帕明的转运依赖于 OCT1 基因型；然而，斯帕嗪的药代动力学与 OCT1 基因型无关。
一些是 CYP2D6 底物的药物也是 OCT 和 MATE1 的底物，表明存在重叠的特异性。广泛代谢和中间代谢者中斯帕嗪羟化的变异性不能用 OCT1 遗传变异来解释，表明存在其他因素。去甲右苯氧胺、苯海拉明和哌泊噻嗪的剂量依赖性毒性似乎与 OCT 和 MATE 无关。
