Disposition of debrisoquine in Caucasians with different CYP2D6-genotypes including those with multiple genes
Disposition of debrisoquine in Caucasians with different CYP2D6-genotypes including those with multiple genes
复制标题
DOI：
10.1097/01213011-199912000-00004
复制
发表时间：
1999-12-01
期刊：
影响因子：
--
通讯作者：
Wilkinson, GR
中科院分区：
文献类型：
--
作者：
Dalén, P;Dahl, ML;Wilkinson, GR
异喹胍是一种主要的原型体内探针，用于基于原型药物及其4-羟基代谢物（所谓的代谢比）的0-8 h尿液排泄评估人体中的多态性CYP 2D 6活性。本研究的主要目的是通过确定药物在选定的健康瑞典白人个体组中的总体分布特征，进一步研究基因型和表型之间的关系。对5名无功能性CYP 2D 6基因的慢代谢者、5名杂合子快代谢者、5名纯合子快代谢者、5名具有重复/三重CYP 2D 6 *2基因的超速代谢者和1名具有13个CYP 2D 6 *2拷贝的个体经口给予异喹（20 mg）。异喹胍和4-羟基异喹胍的血浆峰浓度在2-4小时内达到，然后在96小时内以多指数方式下降，然而，消除过程的后8小时期间的特征在于不规则波动，这妨碍了正式的药代动力学分析。然而，CYP 2D 6基因型之间化合物的血浆水平-时间曲线存在明显差异。例如，在异喹胍的情况下，AUC（0-8）值的平均比率为22：22：7：6：1，对应于0、1、2、3/4和13个基因，并且对于4-羟基异喹胍，相应的值为1：7：19：28：17。不同基因型之间0-96 h异喹胍的尿回收率相差100倍，在弱代谢者中基本上完全回收，在具有13个CYP 2D 6 *2基因的个体中为零。4-羟基异喹排泄根据功能性CYP 2D 6基因的数量增加。异喹胍与4-羟基异喹胍的血浆AUC（0-8）比值与0-8 h尿代谢比值之间存在高度显著相关性（r（s）= 0.95，P < 0.001）。本研究表明，功能性CYP 2D 6等位基因的数量在异喹胍及其CYP 2D 6介导的4-羟基代谢物的血浆浓度-时间曲线中至关重要。浓度相关的药理学效应预计也会受到基因剂量的类似影响，同样的情况可能也适用于其他药物，这些药物的消除主要由这种酶决定;例如，许多抗抑郁药和神经安定药、抗抑郁药、β-肾上腺素受体拮抗剂和阿片类药物。药物遗传学9：697-706（C）1999 Lippincott威廉姆斯&威尔金斯。
Debrisoquine is a major prototypic in-vivo probe used to assess polymorphic CYP2D6 activity in humans, based on the 0-8 h urinary excretion of unchanged drug and its 4-hydroxy metabolite (the so-called metabolic ratio). The primary purpose of the study was to investigate further the relationship between genotype and phenotype by determining the overall disposition characteristics of the drug in selected groups of healthy Swedish Caucasian individuals. Debrisoquine (20 mg) was orally administered to five poor metabolizers with no functional CYP2D6 gene, five heterozygous extensive metabolizers, five homozygous extensive metabolizers, five ultrarapid metabolizers with duplicated/triplicated CYP2D6*2 genes and one individual with 13 copies of CYP2D6*2. Peak plasma levels of debrisoquine and 4-hydroxydebrisoquine were attained within 2-4 h and then declined in a multi-exponential fashion over 96 h, However, the post 8-h period of the elimination process was characterized by irregular fluctuations that prevented formal pharmacokinetic analysis. Nevertheless, marked differences were apparent in the compounds' plasma level-time profiles between the CYP2D6 genotypes. For example, in the case of debrisoquine, the mean ratio of the AUC(0-8) values was 22:22:7:6:1, corresponding to 0, 1, 2, 3/4 and 13 genes and, for 4-hydroxydebrisoquine, the respective values were 1:7:19:28:17. The 0-96 h urinary recovery of debrisoquine differed 100-fold between the genotypes, being essentially complete in poor metabolizers and zero in the individual with 13 CYP2D6*2 genes. 4-hydroxydebrisoquine excretion increased according to the number of functional CYP2D6 genes. A highly significant correlation (r(s) = 0.95, P < 0.001) was observed between the plasma AUC(0-8) ratio for debrisoquine to 4-hydroxydebrisoquine and the 0-8 h urinary metabolic ratio. This study demonstrates that the number of functional CYP2D6 alleles is critically important in the plasma concentration-time curves of debrisoquine and its CYP2D6-mediated 4-hydroxy metabolite. Concentration-related pharmacologic effects would be expected to be similarly affected by gene dosage and it is likely that the same situation also apples to other drugs whose elimination is importantly determined by this enzyme; for example, many antidepressants and neuroleptics, antiarrhythmic agents, beta-adrenoceptor antagonists and opiates. Pharmacogenetics 9:697-706 (C) 1999 Lippincott Williams & Wilkins.