M. Chen, L. Ma, G. L. Drusano, J. S. Bertino, Jr., A. N. Nafziger, Ordway Research Institute, Albany, NY 12208
Background: Studies examining sex differences in CYP3A activity have produced conflicting results. Midazolam (MDZ) is a common biomarker for hepatic and/or intestinal basal CYP3A metabolic activity. We investigated whether sex differences exist in intravenous (IV) or oral (PO) MDZ pharmacokinetics (PK) in healthy volunteers.
Methods: Data from 13 previous studies, conducted from 1996 to 2004, were used. A single dose of IV MDZ (0.025 mg/kg) was administered to 66 healthy white adults (37W/29M, 36.3 ± 7.7 yr). A single dose of PO MDZ 0.075 mg/kg, 0.15 mg/kg (1 study) or 5mg (1 study), was administered to 72 healthy adults (71white/1Asian, 37W/35M, 38.3 ± 8.9 yr). Plasma concentrations were collected at various time points and assayed by LC-MS-MS. PK parameters were determined via population methods using a nonparametric adaptive grid program (NPAG) and a 2 compartment IV or 1 compartment oral absorption model. A Bayesian method was used to calculate each subject's PK. The unpaired t-test was used to compare IV and PO MDZ clearance by sex.
Results: MDZ clearance was significantly higher in women compared to men for both IV (0.497 ± 0.082 L/hr/kg vs. 0.443 ± 0.070 L/hr/kg) and oral administration (0.688 ± 0.279 L/hr/kg vs. 0.536 ± 0.166 L/hr/kg), respectively (p=0.006).
Conclusions: Women showed significantly higher clearance for IV and oral MDZ of 12 and 28%, respectively. Our results suggest women have greater hepatic and intestinal CYP3A isozyme activity. The clinical significance of these findings warrants further genotype and phenotype analysis by sex.