Kashuba A D, Nafziger A N, Kearns G L, Leeder J S, Shirey C S, Gotschall R, Gaedigk A, Bertino J S
Clinical Pharmacology Research Center, Bassett Healthcare, Cooperstown, New York, USA.
Pharmacogenetics. 1998 Oct;8(5):403-10. doi: 10.1097/00008571-199810000-00005.
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.
通过右美沙芬表型分析评估了20名高加索正常志愿者体内的个体内变异性以及月经周期阶段对CYP2D6活性的影响。给10名男性每14天服用30毫克右美沙芬，持续3个月；给10名绝经前女性在每个月经周期的卵泡中期和黄体中期各服用3个完整周期。过夜收集尿液后获得尿右美沙芬/右啡烷摩尔比。10名女性和9名男性为广泛代谢型，1名男性为慢代谢型（通过基因分型确认）。月经周期卵泡中期（均值±标准差：0.00728±0.00717）和黄体中期（0.00745±0.00815）之间右美沙芬代谢比无差异（P = 0.88）。此外，两个阶段之间代谢比的个体内变异性也无显著差异（P = 0.80）。男性（0.00537±0.00431）和女性（0.00737±0.00983）广泛代谢者之间CYP2D6活性无统计学显著的性别差异（P = 0.84）。对于所有个体，右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%。由于月经周期卵泡中期和黄体中期的激素波动似乎不影响CYP2D6活性，CYP2D6底物活性的药代动力学或临床研究可能不需要按月经周期阶段分层。由于基线代谢比平均可能波动37%，当通过右美沙芬测量给定药物对CYP2D6活性的影响时，应重复进行基线和治疗表型评估以准确确定其作用。
