TY - JOUR T1 - Relationship between Hepatic Cytochrome P450 3A Content and Activity and the Disposition of Midazolam Administered Orally JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 110 LP - 114 VL - 26 IS - 2 AU - C. Wandel AU - R. H. Böcker AU - H. Böhrer AU - J. X. deVries AU - W. Hofmann AU - K. Walter AU - B. Kleingeist AU - S. Neff AU - R. Ding AU - I. Walter-Sack AU - E. Martin Y1 - 1998/02/01 UR - http://dmd.aspetjournals.org/content/26/2/110.abstract N2 - It was recently shown by others that the clearance of midazolam/kg body weight after iv administration correlates with hepatic cytochrome P450 (CYP or P450) 3A content in liver transplant patients. However, after po administration midazolam undergoes significant first-pass metabolism, with significant intestinal extraction. The relationship between hepatic CYP3A and midazolam disposition after po administration had not previously been investigated. The aim of this study was to compare intraindividually hepatic CYP3A content and activity with thein vivo pharmacokinetics of midazolam (7.5 mg) administered po. For 15 patients scheduled for partial liver resection, the AUC values for the observed time period (AUC0–5hr) and to infinity (AUCinf) and the clearance were determined. In a macroscopically normal area of resected liver tissue, the microsomal CYP3A4 content (nanomoles per nanomole of total P450) was measured by immunoblot analysis and parameters (apparentVmax, apparentKM , and intrinsic clearance) for the microsomal α-hydroxylation of midazolam were determined. Clearance/kgin vivo correlated with the apparentVmax (r2 = 0.45, p < 0.01) and the CYP3A4 content (r2 = 0.29, p < 0.05). We conclude that interindividual variability in the pharmacokinetics of po administered midazolam is in part determined by interindividual variability in the hepatic microsomalVmax for the α-hydroxylation of midazolam. However, the relationship between the disposition of midazolam administered po and hepatic CYP3A content is weaker than that reported after iv administration, indicating the importance of the contribution of intestinal CYP3A to the in vivo disposition of midazolam administered po. The American Society for Pharmacology and Experimental Therapeutics ER -