Abstract
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.
Footnotes
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Send reprint requests to: Christoph Wandel, M.D., Division of Clinical Pharmacology, Vanderbilt University, Nashville, TN 37232.
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This work was supported in part by Hoffmann-LaRoche AG (Grenzach-Wyhlen, Germany).
- Abbreviation used is::
- P450 or CYP
- cytochrome P450
- Received January 31, 1997.
- Accepted October 6, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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