Differentiation of intestinal and hepatic cytochrome P450 3A activity withuse of midazolam as an in vivo probe: Effect of ketoconazole

Background: The cytochrome P450 3A (CYP3A) isoforms are responsible for the metabolism of a majority of therapeutic compounds, and they are abundant i n the intestine and liver. CYP3A activity is highly variable, causing diffi culty in the therapeutic use of CYP3A substrates. A practical in vivo probe method that characterizes both intestinal and hepatic CYP3A activity would be useful. Objectives: To determine the intestinal and hepatic contribution to the bio availability of midazolam with use of the CYP3A inhibitor ketoconazole. Methods: The pharmacokinetics of midazolam was assessed in nine (six men an d three women) healthy individuals after single doses of 2 mg intravenous a nd 6 mg oral midazolam (phase I). These pharmacokinetic values were compare d with those obtained after single doses of 2 mg intravenous and 6 mg oral midazolam and three doses of 200 mg oral ketoconazole (phase II), Results: After ketoconazole therapy, area under the concentration versus ti me curve of midazolam increased 5-fold after intravenous midazolam administ ration (P less than or equal to .001) and 16-fold after oral midazolam admi nistration (P less than or equal to .001). Intrinsic clearance decreased by 84% (P = .003), Total bioavailability increased from 25% to 80% (P < .001) . The intestinal component of midazolam bioavailability increased to a grea ter extent than the hepatic component (2.3-fold [P = .003] and 1.5-fold [P less than or equal to .001], respectively). In the control phase, female su bjects had greater midazolam clearance values than the male subjects. Conclusions: Ketoconazole caused marked inhibition of CYP3A activity that w as greater in the intestine than the liver. Administration of single doses of oral and intravenous midazolam with and without oral ketoconazole exempl ifies a practical method for differentiating intestinal and hepatic CYP3A a ctivity.