The relative susceptibility of intestinal and hepatic cytochrome P450 (CYP) 3A to induction by rifampin (INN, rifampicin), as a function of age and sex, was investigated with the CYP3A substrate midazolam. Methods. Fourteen young women (mean age, 26 +/- 4 years), 14 young men (mean age, 27 +/- 4 years), 14 elderly women (mean age, 72 5 years), and 10 elderly men (mean age, 70 4 years) received simultaneous intravenous doses (0.05 mg/kg over a 30-minute period) and oral doses of midazolam (3-8 mg of a stable isotope, N-15(3)-midazolam) before and after 7 days of rifampin dosing (600 mg once daily in the evening). Serum and urine samples were assayed for midazolam, N-15(3)-midazolam, and metabolites by liquid chromatography-mass spectrometry. Results. No significant difference (P greater than or equal to .05) in the baseline systemic and oral clearance of midazolam was observed between male and female or young and old volunteers. Rifampin significantly (P < .0001) increased the systemic and oral clearance of midazolam from 0.44 +/- 0.2 L . h/kg and 1.56 0.8 L - h/kg to 0.96 0.3 L . h/kg and 34.4 +/- 21.2 L . h/kg, respectively. Likewise, the oral clearance of midazolam was significantly (P < .0001) increased in women and men, from 1.64 +/- 0.87 L . kg/h and 1.46 0.7 L . kg/h to 28.4 +/- 13.2 L . kg/h and 41.6 +/- 26.5 L . kg/h, respectively. A significant (P =.0023) effect of sex was noted in the extent of induction of the oral clearance of midazolam, being greater in men than in women. In contrast, the extent of midazolam systemic clearance induction was greater in women than in men (P = .0107). Age did not influence the extent of intestinal and hepatic CYP3A induction as determined by the oral and systemic clearance of midazolam. Rifampin dosing significantly (P < .0001) reduced the oral availability by 88%, from 0.32 +/- 0.13 to 0.04 +/- 0.02. Correspondingly, hepatic and intestinal availabilities were significantly (P < .0001) reduced after rifampin administration. After rifampin, the correlation coefficient for the relationship between oral availability and intestinal availability was significantly (P < .0001) reduced from 0.96 to 0.67, which reflects the increasing contribution of hepatic extraction to the determination of midazolam oral availability. A significant nonlinear inverse relationship was observed between the percent change in systemic clearance of miclazolarn and the initial baseline midazolarn systemic clearance (r = -0.68, N = 52, P < .0001). Likewise, a significant inverse relationship was observed between the percent change in oral clearance and the baseline oral clearance v = -0.39, N = 52, P.0041). A significant inverse relationship between the ratio of hepatic intrinsic clearance in the presence of drifampin to that in the absence of rifampin and the corresponding ratio of intestinal intrinsic clearance was observed (Spearman correlation coefficient [r] = -0.68, P < .0001) and indicates that in a given individual the extent of induction was high at either the hepatic or the intestinal site but not both. Conclusion: Sex-related differences exist in the extent of intestinal and hepatic CYP3A induction by rifampin. The extent of induction at hepatic and intestinal sites was inversely dependent and reflected the independent regulation of CYP3A expression at these sites. The large interindividual variation in the extent of induction is explained in part by the variation in baseline expression of CYP3A. Sex-related differences in response to CYP3A inducers will be substrate-dependent and reflect the relative contribution of hepatic and intestinal sites of metabolism.
