RT Journal Article
SR Electronic
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
FD American Society for Pharmacology and Experimental Therapeutics
SP 110
OP 114
VO 26
IS 2
A1 C. Wandel
A1 R. H. Böcker
A1 H. Böhrer
A1 J. X. deVries
A1 W. Hofmann
A1 K. Walter
A1 B. Kleingeist
A1 S. Neff
A1 R. Ding
A1 I. Walter-Sack
A1 E. Martin
YR 1998
UL http://dmd.aspetjournals.org/content/26/2/110.abstract
AB 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