Quantification of intraindividual variability and the influence of menstrual cycle phase on CYP2D6 activity as measured by dextromethorphan phenotyping
Quantification of intraindividual variability and the influence of menstrual cycle phase on CYP2D6 activity as measured by dextromethorphan phenotyping
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DOI：
10.1097/00008571-199810000-00005
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发表时间：
1998-10-01
期刊：
影响因子：
--
通讯作者：
Bertino, JS
中科院分区：
文献类型：
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作者：
Kashuba, ADM;Nafziger, AN;Bertino, JS
采用美沙芬表型分析法，对20名正常白种人的CYP 2D 6活性进行了个体内变异性和月经周期时相的影响。右美沙芬30毫克，每14天给予10名男子3个月，并在中期卵泡和中期黄体期的每个月经周期的三个完整的周期10绝经前妇女。在收集过夜尿液后获得尿中右美沙芬/右啡烷摩尔比，10名女性和9名男性为快代谢者表型，1名男性为慢代谢者表型（通过基因分型确认）。在月经周期的卵泡中期（平均值+/- SD：0.00728 +/- 0.00717）和黄体中期（0.00745 +/- 0.00815）之间，美沙芬代谢率没有差异（P = 0.88）。此外，两个阶段之间的代谢率的个体内变异性没有显着差异（P = 0.80）。在男性（0.00537 +/- 0.00431）和女性（0.00737 +/- 0.00983）快代谢者之间未发现CYP 2D 6活性的统计学显著性别差异（P = 0.84）。对于所有个体，美沙芬比值的个体内变异性范围为12.1-136.6%，中位数为36.7%。由于月经周期中卵泡中期和黄体中期的激素波动似乎不影响CYP 2D 6活性，因此CYP 2D 6底物活性的药代动力学或临床研究可能不需要月经周期阶段分层。因为基线代谢率可能平均波动37%，所以应当获得重复的基线和治疗表型评估，以准确确定给定药物对CYP 2D 6活性的影响，当通过二甲双胍甲啡烷（Pharmacogenetics）8：403-410（C）1998 Lippincott威廉姆斯和威尔金斯（Wilkins）测量时。
Intraindividual variability and the effects of menstrual cycle phase on CYP2D6 activity were evaluated by dextromethorphan phenotyping in 20 Caucasian normal volunteers. Dextromethorphan 30 mg was administered to 10 men every 14 days for 3 months, and to 10 premenopausal women during the mid-follicular and mid-luteal phases of each menstrual cycle for three complete cycles. Urinary dextromethorphan/dextrorphan molar ratios were obtained after an overnight urine collection, Ten women and nine men were extensive metabolizer phenotypes, and one man was a poor metabolizer phenotype (confirmed by genotyping). There was no difference in dextromethorphan metabolic ratios between the mid-follicular (mean +/- SD: 0.00728 +/- 0.00717) and mid-luteal (0.00745 +/- 0.00815) phases of the menstrual cycle (P = 0.88). Also, no significant difference was found in the intraindividual variability of the metabolic ratios between the two phases (P = 0.80). No statistically significant sex difference in CYP2D6 activity was found between men (0.00537 +/- 0.00431) and women (0.00737 +/- 0.00983) extensive metabolizers (P = 0.84). For all individuals, intraindividual variability in dextromethorphan ratios ranged from 12.1-136.6% with a median of 36.7%. Because hormonal fluctuations within the mid-follicular and mid-luteal phases of the menstrual cycle do not appear to affect CYP2D6 activity, pharmacokinetic or clinical investigations of CYP2D6 substrate activity may not require menstrual cycle phase stratification. Because baseline metabolic ratios may fluctuate an average of 37%, repeat baseline and treatment phenotyping assessments should be obtained for accurate determination of a given drug's effect on CYP2D6 activity when measured by dextromethorphan, Pharmacogenetics 8:403-410 (C) 1998 Lippincott Williams & Wilkins.