Distribution of Exogenous and Endogenous CYP3A Markers and Related Factors in Healthy Males and Females

Cytochrome P450 (CYP) 3A is an important drug-metabolizing enzyme in humans. Assessing CYP3A activity is necessary for predicting therapeutic outcomes or the potential adverse events of various therapeutics. This study sought to evaluate the distribution of endogenous and exogenous markers reflecting hepatic CYP3A activity and related factors affecting its activity in healthy male and female. Each subject was given a single 1 mg dose of midazolam intravenously. Pharmacokinetics, pharmacometabolomics, and pharmacogenomics analyses were performed to evaluate CYP3A activity. Urinary and plasma steroids were quantified with gas chromatography coupled with triple-quadrupole mass spectrometry (GC-MS), and the concentrations of midazolam and its metabolites were quantified with liquid chromatography coupled with electrospray tandem mass spectrometry (LC-MS/MS). A total of 100 subjects completed this study. Midazolam clearance (MDZ CL) and the metabolic ratio (MDZ MR) were significantly correlated with 6 beta-OH-cortisol/cortisol and 6 beta-OH-cortisone/cortisone. MDZ CL, 6 beta-OH-cortisol/cortisol, and 6 beta-OH-cortisone/cortisone decreased with increasing age (Pearson r = -0.333, -0.329, and -0.528, respectively; P < 0.05). When the markers were compared according to sex, MDZ CL and 6 beta-OH-cortisol/cortisol showed significant difference between sexes. However, MDZ CL was higher in female group than male group and 6 beta-OH-cortisol/cortisol was higher in male group than female group. No significant differences in markers were found when comparing progesterone levels. Our results indicate that both exogenous and endogenous markers showed decreased CYP3A activity with increasing age, which suggested that age could be a factor that significantly influences CYP3A activity.