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首页> 外文期刊>The Journal of Clinical Pharmacology: Official Journal of the American College of Clinical Pharmacology >Nortriptyline E-10-hydroxylation in vitro is mediated by human CYP2D6 (high affinity) and CYP3A4 (low affinity): implications for interactions with enzyme-inducing drugs.
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Nortriptyline E-10-hydroxylation in vitro is mediated by human CYP2D6 (high affinity) and CYP3A4 (low affinity): implications for interactions with enzyme-inducing drugs.

机译：体外去甲替林E-10-羟基化作用是由人CYP2D6（高亲和力）和CYP3A4（低亲和力）介导的：与酶诱导药物相互作用的意义。

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摘要

The human cytochrome P450 (CYP) isoforms mediating nortriptyline 10-hydroxylation have been identified using kinetic studies on heterologously expressed human CYPs and chemical inhibition studies on human liver microsomes. Nortriptyline was metabolized to E-10-hydroxynortriptyline by human lymphoblast-expressed CYPs 2D6 (Km 2.1 microM) and 3A4 (Km 37.4 microM) with high and low affinity, respectively, whereas CYPs 1A2, 2A6, 2B6, 2C9, 2C19, and 2E1 had no detectable activity. Human liver microsomal nortriptyline E-10-hydroxylation displayed biphasic kinetics. The high-affinity component (Km 1.3 +/- 0.4 microM, n = 11 livers) was selectively inhibited by the CYP 2D6 inhibitor quinidine, whereas the CYP3A4 inhibitor ketoconazole selectively inhibited the low-affinity component (K(m) 24.4 +/- 7 microM, n = 11 livers). Inhibition by ketoconazole increased with increasing substrate concentration, whereas the reverse was true for quinidine. The Vmax of the low-affinity component in human liver microsomes was significantly correlated (r2 = 0.84) with the relative activity factor for CYP3A4, a measure of the amount of catalytically active enzyme. A simulation of the relative contribution of CYPs 2D6 and 3A4 to net nortriptyline hydroxylation rate suggested that the relative contribution of CYP3A4 is only 20% even at the higher end of the therapeutic range. Induction of CYP3A4 will increase its importance and increase the net metabolic rate, whereas inhibition of CYP3A4 will be of little importance due to its minimal relative contribution under uninduced conditions. The identification of CYP3A4 as a low-affinity nortriptyline E-10-hydroxylase explains the ability of poor metabolizers of debrisoquin to hydroxylate nortriptyline, as well as the increased in vivo clearance via this pathway caused by CYP3A4-inducing drugs such as pentobarbital, carbamazepine, and rifampin.
机译：使用异源表达的人CYP的动力学研究和对人肝微粒体的化学抑制研究，已经鉴定了介导去甲替林10-羟基化的人细胞色素P450（CYP）同工型。人成淋巴细胞表达的CYP 2D6（Km 2.1 microM）和3A4（Km 37.4 microM）分别以高亲和力和低亲和力将去甲替林代谢为E-10-羟基去甲替林。而CYP 1A2、2A6、2B6、2C9、2C19和2E1没有可检测的活动。人肝微粒体去甲替林碱E-10-羟基化显示出双相动力学。高亲和力组分（Km 1.3 +/- 0.4 microM，n = 11肝脏）被CYP 2D6抑制剂奎尼丁选择性抑制，而CYP3A4抑制剂酮康唑则选择性抑制低亲和力组分（K（m）24.4 +/- 7 microM，n = 11个肝脏）。酮康唑的抑制作用随底物浓度的增加而增加，而奎尼丁则相反。人肝微粒体中低亲和力组分的Vmax与CYP3A4的相对活性因子显着相关（r2 = 0.84），CYP3A4是一种催化活性酶的量度。 CYP 2D6和3A4对净去甲替林羟化率的相对贡献的模拟表明，即使在治疗范围的较高端，CYP3A4的相对贡献也仅为20％。 CYP3A4的诱导将增加其重要性并增加净代谢率，而CYP3A4的抑制因在未诱导条件下其相对贡献最小而将不重要。将CYP3A4识别为低亲和力的去甲替林E-10-羟化酶可以解释debrisoquin弱代谢者羟化去甲替林的能力，以及通过CYP3A4诱导药物如戊巴比妥，卡马西平，和利福平。

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