Lack of Gender Differences and Large Intrasubject Variability in Cytochrome P450 Activity Measured by Phenotyping with Dextromethorphan

Abstract

Gender-based differences in cytochrome P450 (CYP) activity may occur due to endogenous hormonal fluctuations with the menstrual cycle, which are altered by oral contraceptives. This study assessed the average activity and within-subject variability in CYP3A4 and CYP2D6 in men, women taking Triphasil, and regularly menstruating women not receiving oral contraceptives. Thirty-three healthy volunteers participated in this 28-day pilot study (12 women receiving Triphasil) (OCs), 11 regularly menstruating women not on exogenous progesterone or estrogen (no OCs), and 10 men. CYP3A4 and CYP2D6 activities were phenotyped with dextromethorphan (DM) on study days 7, 14, 21, and 28 using urinary ratios of DM:3-methoxymorphinan (3MM) and DM:dextrorphan (DX), respectively. Serial blood concentrations of estrogen and progesterone and menstrual diaries were used to determine menstrual phase in both groups of women. Average urinary DM:3MM and DM:DX in the 28 extensive metabolizers of CYP2D6 did not differ between the three study populations (p = 0.86 and 0.93, respectively). Post hoc power analysis indicated that more than 1000 subjects would be needed for 80% power (alpha = 0.05) to detect a +/- 15% difference from the population mean in the urinary ratios of dextromethorphan and its metabolites 3MM and DX. Variability in CYP3A4 and CYP2D6 activity, characterized by intrasubject standard deviation, also did not differ. The varying doses of levonorgesterol and ethinyl estradiol in Triphasil, fluctuations in estrogen and progesterone, and menstrual phase did not influence CYP3A4 or CYP2D6 activity. It was concluded that CYP3A4 and CYP2D6 activity and intrasubject variability were not different in the three study populations, and thus a clinically important difference between men, women on Triphasil, and women not receiving oral contraceptives is unlikely. High inter- and intrasubject variability in DM:3MM and DM:DX were clearly demonstrated and limit the use of dextromethorphan to phenotype endogenous CYP3A4 and CYP2D6 activity.

The effect of CYP2J2, CYP3A4, CYP3A5 and the MDR1 C3435T polymorphisms and gender on the urinary excretion of the metabolites of the H1‐receptor antihistamine ebastine: a pilot study

“…The main enzymes responsible for ebastine metabolism, CYP3A and CYP2J2, are present in intestine [7,26,27], where their activity could be contributing to the first pass metabolism of ebastine and to the large interindividual variability observed [7]. Our findings indicated that urine excretion of the CYP3A-generated metabolite, desalkylebastine, displayed a three-fold higher variability than that of carebastine, which is consistent with the large variation observed in the urinary excretion of other substrates metabolized by CYP3A [29,30].…”

A Transgenic Mouse Model With a Luciferase Reporter for Studying in Vivo Transcriptional Regulation of the Human Cyp3a4 Gene

“…Some studies have shown that CYP3A4 activity is higher in women than in men (Harris et al, 1995), but others described no major gender-specific differences in CYP3A activity (McCune et al, 2001;Meibohm et al, 2002). To explain the gender differences in the CYP3A4-luc transgene expression in transgenic mice, we speculate that androgen response element (ARE)-like sequences existing in the 5Ј flanking region of CYP3A4 gene may be functionally activated by androgens in mice, but not in humans.…”

Liquid chromatography/tandem mass spectrometry method for simultaneous evaluation of activities of five cytochrome P450s using a five-drug cocktail and application to cytochrome P450 phenotyping studies in rats

“…The total urinary recovery of 4 -hydroxymephenytoin in 0-6 h urine was used as the phenotypic measure of CYP2C19 activity [27]. The activity of CYP2D6 was accessed by the dextromethorphan urinary metabolic ratio, calculated as the ratio of amount of dextromethorphan to dextrorphan recovered in 0-6 h urine [28][29][30].…”