10-hydroxylation of nortriptyline in white persons with 0, 1, 2, 3, and 13 functional CΥP2D6 genes
10-hydroxylation of nortriptyline in white persons with 0, 1, 2, 3, and 13 functional CΥP2D6 genes
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DOI：
10.1016/s0009-9236(98)90040-6
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发表时间：
1998-04-01
影响因子：
6.7
通讯作者：
Bertilsson, L
中科院分区：
文献类型：
--
作者：
Dalén, P;Dahl, ML;Bertilsson, L
目的：研究去甲替林及其主要代谢产物10-羟基去甲替林在不同CYP 2D 6基因型的白色受试者（包括重复和多重重复CYP 2D 6 *2基因的受试者）中的分布和作用，并评估功能性CYP 2D 6等位基因数量对去甲替林代谢的贡献，在此用作CYP 2D 6底物的模型药物。口服单剂量25至50毫克去甲替林给予五个弱代谢的异喹（INN，异喹胍）无功能性CYP 2D 6基因，5种快代谢型有1种功能性CYP 2D 6基因，5种快代谢型有2种功能性CYP 2D 6基因，5种超快代谢型有重复CYP 2D 6 *2基因，和一个具有13个CYP 2D 6 *2基因拷贝的超快速代谢者。分析去甲替林和10-羟基去甲替林的血浆动力学。测定了抗胆碱能作用（抑制流涎和调节障碍）、镇静、血压以及对仰卧位和直立位脉率的影响。结果：CYP 2D 6基因型与去甲替林和10-羟基去甲替林的血药动力学密切相关。在具有0、1、2、3和13个功能基因的组中，去甲替林的表观口服清除率之间的比例为1：1：4：5：17。在具有0、1、2、3和13个功能基因的组中，AUC（去甲替林）与AUC（10-羟基去甲替林）比值之间的比例为36：25：10：4：1。去甲替林的口服血浆清除率和AUC（去甲替林）/AUC（10-羟基去甲替林）比值与异喹喹代谢率显著相关（r（s）=-0.89，p = 0.0001; r（s）= 0.92，P = 0.0001）。虽然ultrarapid代谢受试者给予两倍的去甲替林剂量（50毫克），抑制流涎并没有更明显的相比，其他基因型组给予25毫克nortriptyline.Conclusion：本研究的结果显示定量的重要性的CYP 2D 6基因型，特别是存在多功能CYP 2D 6酶的去甲替林和10-hydroxynortriptyline的药代动力学。具有多个功能基因拷贝的受试者的基因分型对于区分超速代谢者和不遵守处方的患者以及确保这些患者有足够的药物选择和剂量可能具有重要价值。
Objective: To investigate the disposition and effects of nortriptyline and its major metabolite 10-hydroxynortriptyline in panels of white subjects with different CYP2D6 genotypes, including those with duplicated and multiduplicated CYP2D6*2 genes and to evaluate the contribution of the number of functional CYP2D6 alleles to the metabolism of nortriptyline, used here as a model drug for CYP2D6 substrates.Methods: Oral single doses of 25 to 50 mg nortriptyline were given to five poor metabolizers of debrisoquin (INN, debrisoquine) with no functional CYP2D6 gene, five extensive metabolizers with one functional CYP2D6 gene, five extensive metabolizers with two functional CYP2D6 genes, five ultrarapid metabolizers with duplicated CYP2D6*2 genes, and one ultrarapid metabolizer with 13 copies of the CYP2D6*2 gene. Plasma kinetics of nortriptyline and 10-hydroxynortriptyline were analyzed. Anticholinergic effects (inhibition of salivation and accommodation disturbances), sedation, blood pressure, and effect on supine and erect pulse rate were measured. Results: There was a dear relation between the CYP2D6 genotype and the plasma kinetics of nortriptyline and 10-hydroxynortriptyline. The proportion between the apparent oral clearances of nortriptyline in the groups with 0, 1, 2, 3, and 13 functional genes was 1:1:4:5:17. The proportions between AUC(nortriptyline) to AUC(10-hydroxynortriptyline) ratios in the groups with 0, 1, 2, 3, and 13 functional genes were 36:25:10:4:1. Oral plasma clearance of nortriptyline and AUC(nortriptyline) to AUC(10-hydroxynortriptyline) ratio bath correlated significantly with the debrisoquin metabolic ratio (r(s) = -0.89, p = 0.0001; r(s) = 0.92, P = 0.0001). Although ultrarapid metabolizer subjects were given double the nortriptyline dose (50 mg), inhibition of salivation was not more pronounced compared with the other genotype groups given 25 mg nortriptyline.Conclusion: The results of this study show the quantitative importance of the CYP2D6 genotype, especially the presence of multiple functional CYP2D6 gents for the pharmacokinetics of nortriptyline and 10-hydroxynortriptyline. Genotyping of subjects with multiple copies of functional genes may be of great value for differentiating ultrarapid metabolizers from patients who do not comply with the prescription and for assuring adequate drug choice and dosage for these patients.