Untitled

Abstract

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.

The Anti-Ischemic Effect of Metoprolol in Patients with Chronic Angina Pectoris Is Gender-Specific

“…Metoprolol increased time to angina and to ST depression during ergometry in both groups, slightly more so in men than in women but the difference did not reach significance. One should, however, bear in mind the limited number of patients in our study and there is at least the possibility that the difference of men versus women might reach significance with an adequate number of patients, such as the values seen in the multicenter studies [12,13,14,15,16,17,18,19,20,21,22]. On the other hand, even within the small number of patients, metoprolol decreased exercise blood pressure, heart rate and RPP much more in the men than in the women, and as a consequence exercise time and the METS values during exercise were significantly higher in men.…”

“…In our patients the body weight of the women was slightly less (–9%) than that of the men and the daily dose of metoprolol was similar in both groups (men vs. women, p = 0.88). Thus, according to pharmacokinetics [11,14,15,16], women should have obtained higher plasma levels of this drug and the ensuing pharmacologic effects of metoprolol should have been greater. Our results do not confirm this assumption.…”

“…Women treated with β-blockers demonstrate a more pronounced decrease in heart rate and systolic blood pressure, and experience significantly smaller increases in exercise heart rates than do men [12,13,14,15,16]. The β 1 -selective blocker metoprolol is primarily metabolized via CYP2D6: even after normalization for body weight, men have a greater activity of this enzyme and a faster clearance of metoprolol.…”

“…The β 1 -selective blocker metoprolol is primarily metabolized via CYP2D6: even after normalization for body weight, men have a greater activity of this enzyme and a faster clearance of metoprolol. In contrast, women have a significantly lower peripheral volume of distribution and significantly higher plasma levels, maximal concentrations are approximately 100% above those of men [14,15,16,17]. Drug exposure to metoprolol also increases with oral contraceptives [11,14,15,16].…”

“…In contrast, women have a significantly lower peripheral volume of distribution and significantly higher plasma levels, maximal concentrations are approximately 100% above those of men [14,15,16,17]. Drug exposure to metoprolol also increases with oral contraceptives [11,14,15,16]. Studies of β-blocker therapy in secondary cardiovascular prevention after myocardial infarction have not demonstrated clear gender-specific differences [18, 19].…”