CYP2D6 介导体外可乐定的 4-羟化作用：提示妊娠引起可乐定清除率的变化。
CYP2D6 mediates 4-hydroxylation of clonidine in vitro: implication for pregnancy-induced changes in clonidine clearance.
机构信息
Department of Pharmacy, University of Washington Health Sciences Center, 1959 NE Pacific Street, Seattle, WA 98195-7630, USA.
出版信息
Drug Metab Dispos. 2010 Sep;38(9):1393-6. doi: 10.1124/dmd.110.033878. Epub 2010 Jun 22.
Abstract
Clonidine is a centrally acting, alpha-2 adrenergic agonist used for the treatment of hypertension during pregnancy. The metabolic pathways of clonidine are poorly understood, and the quantitative contribution of specific human cytochrome P450 (P450) isoforms has not been systematically assessed. In this study, 17 cDNA-expressed P450 enzymes, in addition to pooled human liver microsomes, were evaluated for clonidine 4-hydroxylation activity in vitro. Five P450 enzymes-CYP2D6, 1A2, 3A4, 1A1, and 3A5-catalyzed measurable formation of 4-hydroxyclonidine. Selective inhibition studies in human liver microsomes confirmed that these isoforms are jointly responsible for 4-hydroxylation of clonidine in vitro, and CYP2D6 accounted for approximately two-thirds of the activity. The major role of CYP2D6 in clonidine metabolism might explain the increase in its nonrenal clearance during pregnancy.
摘要
可乐定是一种作用于中枢的α-2 肾上腺素能激动剂，用于治疗妊娠高血压。可乐定的代谢途径尚未完全阐明，特异性人细胞色素 P450（CYP450）同工酶的定量贡献也尚未系统评估。在这项研究中，评估了 17 种 cDNA 表达的 P450 酶以及人肝微粒体，以评估它们在体外对可乐定 4-羟化的活性。5 种 P450 酶（CYP2D6、1A2、3A4、1A1 和 3A5）可催化 4-羟基可乐定的生成。在人肝微粒体中的选择性抑制研究证实，这些同工酶共同负责可乐定的体外 4-羟化，CYP2D6 约占活性的三分之二。CYP2D6 在可乐定代谢中的主要作用可能解释了其在妊娠期间非肾清除率增加的原因。
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本文引用的文献
1
Clonidine pharmacokinetics in pregnancy.可乐定在妊娠期的药代动力学。
Drug Metab Dispos. 2009 Apr;37(4):702-5. doi: 10.1124/dmd.108.024984. Epub 2008 Dec 30.
2
Pregnancy-induced changes in pharmacokinetics: a mechanistic-based approach.妊娠引起的药代动力学变化：基于机制的方法。
Clin Pharmacokinet. 2005;44(10):989-1008. doi: 10.2165/00003088-200544100-00001.
3
Role of pharmacokinetics and metabolism in drug discovery and development.药代动力学和代谢在药物发现与开发中的作用。
Pharmacol Rev. 1997 Dec;49(4):403-49.
4
Induction of CYP2D6 in pregnancy.孕期CYP2D6的诱导
Clin Pharmacol Ther. 1997 Oct;62(4):400-7. doi: 10.1016/S0009-9236(97)90118-1.
5
Central hypotensive effects of the alpha2a-adrenergic receptor subtype.α2a - 肾上腺素能受体亚型的中枢性降压作用。
Science. 1996 Aug 9;273(5276):801-3. doi: 10.1126/science.273.5276.801.
6
Plasma clonidine levels in hypertension.高血压患者的血浆可乐定水平
Clin Pharmacol Ther. 1983 Sep;34(3):341-6. doi: 10.1038/clpt.1983.177.
7
Pregnancy-induced increase in metoprolol metabolism.妊娠引起的美托洛尔代谢增加。
Clin Pharmacol Ther. 1985 Jun;37(6):688-92. doi: 10.1038/clpt.1985.114.
8
Clonidine hydrochloride--a safe and effective antihypertensive agent in pregnancy.盐酸可乐定——一种孕期安全有效的抗高血压药物。
Obstet Gynecol. 1985 Nov;66(5):634-8.
9
Pharmacokinetics and concentration-effect relationships of intervenous and oral clonidine.静脉注射与口服可乐定的药代动力学及浓度-效应关系
Clin Pharmacol Ther. 1977 May;21(5):593-601. doi: 10.1002/cpt1977215593.
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