Xu Ren-ai, Gu Er-min, Zhou Quan, Yuan Lingjing, Hu Xiaoxia, Cai Jianping, Hu Guoxin
Department of Pharmacy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China.
Department of Pharmacology, School of Pharmacy, Wenzhou Medical University, Wenzhou, People's Republic of China.
Drug Des Devel Ther. 2016 Feb 15;10:687-96. doi: 10.2147/DDDT.S97789. eCollection 2016.
CYP2D6 is one of the most important members of the cytochrome P450 superfamily. Its genetic polymorphism significantly influences the efficacy and safety of some drugs, which might cause adverse effects and therapeutic failure.
The aim of this research was mainly to explore the catalytic activities of 22 newly reported CYP2D6 isoforms (2D6*87, *88, *89, *90, *91, *92, *93, *94, *95, 96,97, 98, R25Q, F164L, E215K, F219S, V327M, D336N, V342M, R344Q, R440C, R497C) on dapoxetine in vitro. The research was designed with an appropriate incubation system in test tubes and carried out in the constant temperature water. Through detecting its two metabolites desmethyldapoxetine and dapoxetine-N-oxide, the available data were obtained to explain the influence of CYP2D6 polymorphism on the substrate drug dapoxetine. As a result, the intrinsic clearance (Vmax/Km) values of most variants were significantly altered when compared with the counterpart of CYP2D61, with most of these variants exhibiting either reduced Vmax and/or increased Km values. For dapoxetine demethylation pathway (which produces desmethyldapoxetine), 2D689 and E215K exhibited no markedly decreased relative clearance of 92.81% and 97.70%, respectively. The relative clearance of rest 20 variants exhibited decrease in different levels, ranging from 20.44% to 90.90%. For the dapoxetine oxidation pathway (which produces dapoxetine-N-oxide), the relative clearance values of three variants, 2D690, 94, and V342M, exhibited no markedly increased relative clearance of 106.17%, 107.78%, and 109.98%, respectively; the rest 19 variants exhibited significantly decreased levels ranging from 27.56% to 84.64%. In addition, the kinetic parameters of two CYP2D6 variants (2D692 and 2D696) could not be detected, due to the defect of the CYP2D6 gene.
As the first report of all aforementioned alleles for dapoxetine metabolism, these data may help in the clinical assessment of the metabolic elimination of dapoxetine and may provide fundamental information for further clinical studies.
细胞色素P450超家族中最重要的成员之一是CYP2D6。其基因多态性显著影响某些药物的疗效和安全性，可能导致不良反应和治疗失败。
本研究的主要目的是在体外探究22种新报道的CYP2D6同工型（2D6*87、*88、*89、*90、*91、*92、*93、*94、*95、96、97、98、R25Q、F164L、E215K、F219S、V327M、D336N、V342M、R344Q、R440C、R497C）对达泊西汀的催化活性。研究采用合适的试管孵育系统，并在恒温水浴中进行。通过检测其两种代谢产物去甲基达泊西汀和达泊西汀 - N - 氧化物，获得可用数据以解释CYP2D6基因多态性对底物药物达泊西汀的影响。结果显示，与CYP2D61相比，大多数变异体的内在清除率（Vmax/Km）值有显著改变，这些变异体大多表现出Vmax降低和/或Km值升高。对于达泊西汀去甲基化途径（产生去甲基达泊西汀），2D689和E215K的相对清除率分别未显著降低，为92.81%和97.70%。其余20种变异体的相对清除率在不同程度上降低，范围为20.44%至90.90%。对于达泊西汀氧化途径（产生达泊西汀 - N - 氧化物），三种变异体2D690、94和V342M的相对清除率分别未显著升高，为106.17%、107.78%和109.98%；其余19种变异体的相对清除率显著降低，范围为27.56%至84.64%。此外，由于CYP2D6基因缺陷，无法检测到两种CYP2D6变异体（2D692和2D696）的动力学参数。
作为上述所有等位基因对达泊西汀代谢的首次报道，这些数据可能有助于临床评估达泊西汀的代谢消除情况，并可为进一步的临床研究提供基础信息。
