RELATIONSHIP BETWEEN HEPATIC CYTOCHROME-P450 3A CONTENT AND ACTIVITY AND THE DISPOSITION OF MIDAZOLAM ADMINISTERED ORALLY

It was recently shown by others that the clearance of midazolam/kg bod y weight after iv administration correlates with hepatic cytochrome P4 50 (CYP or P450) 3A content in liver transplant patients. However, aft er po administration midazolam undergoes significant first-pass metabo lism, with significant intestinal extraction. The relationship between hepatic CYP3A and midazolam disposition after po administration had n ot previously been investigated. The aim of this study was to compare intraindividually hepatic CYP3A content and activity with the in vivo pharmacokinetics of midazolam (7.5 mg) administered po. For 15 patient s scheduled for partial liver resection, the AUC values for the observ ed time period (AUC(0-5hr)) and to infinity (AUC(inf)) and the clearan ce were determined. In a macroscopically normal area of resected liver tissue, the microsomal CYP3A4 content (nanomoles per nanomole of tota l P450) was measured by immunoblot analysis and parameters (apparent V -max, apparent K-M, and intrinsic clearance) for the microsomal alpha- hydroxylation of midazolam were determined. Clearance/kg in vivo corre lated with the apparent V-max (r(2) = 0.45, p < 0.01) and the CYP3A4 c ontent (r(2) = 0.29, p < 0.05). We conclude that interindividual varia bility in the pharmacokinetics of pc administered midazolam is in part determined by interindividual variability in the hepatic microsomal V -max for the alpha-hydroxylation of midazolam. However, the relationsh ip between the disposition of midazolam administered po and hepatic CY P3A content is weaker than that reported after iv administration, indi cating the importance of the contribution of intestinal CYP3A to the i n vivo disposition of midazolam administered po.