Labbé L, Sirois C, Pilote S, Arseneault M, Robitaille N M, Turgeon J, Hamelin B A
Faculty of Pharmacy, Laval University, Ste-Foy, Quebec, Canada.
Pharmacogenetics. 2000 Jul;10(5):425-38. doi: 10.1097/00008571-200007000-00006.
The effects of gender, time variables, menstrual cycle phases, plasma sex hormone concentrations and physiologic urinary pH on CYP2D6 phenotyping were studied using two widely employed CYP2D6 probe drugs, namely dextromethorphan and metoprolol. Phenotyping on a single occasion of 150 young, healthy, drug-free women and men revealed that the dextromethorphan: dextrorphan metabolic ratio (MR) was significantly lower (P < 0.0001) in 56 female extensive metabolizers (0.008+/-0.021) compared to 86 male extensive metabolizers (0.020 +/-0.040). Urinary pH was a significant predictor of dextromethorphan: dextrorphan MRs in men and women (P < 0.001). Once-a-month phenotyping with dextromethorphan of 12 healthy young men (eight extensive metabolizers and four poor metabolizers) over a 1-year period, as well as every-other-day phenotyping with dextromethorphan of healthy, pre-menopausal women (10 extensive metabolizers and 2 poor metabolizers) during a complete menstrual cycle, did not follow a particular pattern and showed similar intrasubject variability ranging from 24.1% to 74.5% (mean 50.9%) in men and from 20.5% to 96.2% (mean 52.0%) in women, independent of the CYP2D6 phenotype (P = 0.342). Using metoprolol as a probe drug, considerable intrasubject variability (38.6+/- 12.0%) but no correlation between metoprolol: alpha-hydroxymetoprolol MRs and pre-ovulatory, ovulatory and luteal phases (mean +/- SD metoprolol: a-hydroxymetoprolol MRs: 1.086+/- 1.137 pre-ovulatory; 1.159+/-1.158 ovulatory and 1.002+/-1.405 luteal phase; P> 0.9) or 17beta-oestradiol, progesterone or testosterone plasma concentrations was observed. There was a significant inverse relationship between physiologic urinary pH and sequential dextromethorphan: dextrorphan MRs as well as metoprolol: alpha-hydroxymetoprolol MRs in men and women, with metabolic ratios varying up to six-fold with metoprolol and up to 20-fold with dextromethorphan (ANCOVA P < 0.001). We conclude that apparent CYP2D6 activity is highly variable, independent of menstrual cycle phases, sex hormones, time variables or phenotype. Up to 80% of the observed variability can be explained by variations of urinary pH within the physiological range. An apparent phenotype shift as a result of variations in urinary pH may be observed in individuals who have metabolic ratios close to the population antimode.
使用两种广泛应用的CYP2D6探针药物右美沙芬和美托洛尔，研究了性别、时间变量、月经周期阶段、血浆性激素浓度和生理性尿液pH对CYP2D6表型的影响。对150名年轻、健康、未服用药物的女性和男性进行单次表型分析，结果显示，56名女性广泛代谢者的右美沙芬：右啡烷代谢率（MR）显著低于（P<0.0001）86名男性广泛代谢者（分别为0.008±0.021和0.020±0.040）。尿液pH是男性和女性右美沙芬：右啡烷MR的显著预测因子（P<0.001）。在1年期间，对12名健康年轻男性（8名广泛代谢者和4名慢代谢者）每月进行一次右美沙芬表型分析，以及在一个完整月经周期内对健康的绝经前女性（10名广泛代谢者和2名慢代谢者）每隔一天进行一次右美沙芬表型分析，结果未呈现特定模式，且男性受试者内变异相似，范围为24.1%至74.5%（平均50.9%），女性为20.5%至96.2%（平均52.0%），与CYP2D6表型无关（P=0.342）。使用美托洛尔作为探针药物，受试者内变异较大（38.6±12.0%），但美托洛尔：α-羟基美托洛尔MR与排卵前、排卵期和黄体期（平均±标准差美托洛尔：α-羟基美托洛尔MR：排卵前1.086±1.137；排卵期1.159±1.158；黄体期1.002±1.405；P>0.9）或血浆17β-雌二醇、孕酮或睾酮浓度之间无相关性。在男性和女性中，生理性尿液pH与连续的右美沙芬：右啡烷MR以及美托洛尔：α-羟基美托洛尔MR之间存在显著的负相关，美托洛尔的代谢率变化高达6倍，右美沙芬高达20倍（协方差分析P<0.001）。我们得出结论，表观CYP2D6活性高度可变，与月经周期阶段、性激素、时间变量或表型无关。观察到的变异中高达80%可由生理范围内尿液pH的变化来解释。在代谢率接近人群反众数的个体中，可能会观察到由于尿液pH变化导致的表观表型转变。
