Midazolam and cortisol metabolism before and after CYP3A induction in humans

Introduction: CYP3A is responsible for the metabolism of numerous endogenou s and exogenous compounds. Several substrates of CYP3A. have been investiga ted to assess the CYP3A-metabolizing capacity of an individual in an attemp t to predict the rate of metabolism of other CYP3A substrates. Two such tes ts of CYP3A activity are the midazolam plasma clearance after its intraveno us administration and the 6 beta -OH cortisol urinary ratio. Possible corre lations between these 2 tests were investigated before and after treatment with rifampin in a group of healthy volunteers. Methods: Pharmacokinetic pa rameters of midazolam and 6 beta -OH cortisol urinary ratio were evaluated in 8 volunteers before and after 6 days treatment with rifampin, a potent i nducer of CYP3A, and after cessation of rifampin treatment. Results: Midazo lam systemic clearance and the 6 beta -OH cortisol urinary ratio were signi ficantly higher at Days 7 and 10 than at Day 0. There was a strong positive correlation between these 2 parameters (r = 0.70, p < 0.001). In contrast, no correlation was observed between the ratio of the AUCs of 1'-OH midazol am vs. midazolam (AUC(1'-OH)(0-t)/AUC(MDZ)(0-t)) or the ratio of plasma con centration of 1'-OH midazolam vs. midazolam (C-1'OH(30min)/C-MDZ(30min)) an d the 6 beta -OH cortisol urinay ratio (r= 0.05, p = 0.82; r 0.04, p = 0.88 , respectively). Considering only data obtained before or after treatment w ith rifampin, however, no correlation was observed between midazolam system ic clearance and the 6 beta -OH cortisol urinary ratio. Conclusions: These data demonstrate that there is a strong positive correlation between system ic midazolam clearance and 6 beta -OH cortisol urinary ratio before and aft er induction. This suggests that the 6 beta -OH cortisol urinary ratio test is a non-invasive alternative to the use of systemic midazolam clearance f or monitoring the time-course of CYP3A induction.