110 Propofol is an intravenous anesthetic characterized by very short duration of action. Propofol is frequently used in combination with other drugs such as opioids and midazolam during anesthesia and produces a syn- ergistic hypnotic effect. 1-3 Because propofol inhibits the oxidative metabolism of various agents, 4 a decreased clearance of midazolam by propofol may contribute to the synergistic effect. Although the phar- macokinetic disposition of midazolam has been exten- sively studied, 5-7 to our knowledge, no reports indicat- ing that propofol inhibits the metabolism of midazolam in vivo have been presented. Because a decreased clear- PHARMACOKINETICS AND DRUG DISPOSITION Propofol decreases the clearance of midazolam by inhibiting CYP3A4: An in vivo and in vitro study Objective: To examine the effect of propofol on the pharmacokinetics of midazolam in vivo and to eluci- date the mechanism of the pharmacokinetic changes of midazolam by propofol with the use of human liver microsomes and recombinant CYP3A4. Methods: In an in vivo, double-blind randomized study, 24 patients received 0.2 mg/kg midazolam and either 2 mg/kg propofol (propofol group) or placebo (placebo group) for induction of anesthesia. In the propofol group, continuous infusion of propofol at 9 mg/kg/h was started immediately after the bolus infusion of propofol and was maintained for an hour. In the placebo group the same dose of soybean emulsion as a placebo was given and infused intravenously for an hour instead of propofol. In an in vitro study the effect of propofol on the metabolism of midazolam was studied with human liver microsomes and recombinant CYP3A4. Results: In the propofol group the mean clearance of midazolam was decreased by 37% (P = .005) and the mean elimination half-life was prolonged by 61% (P = .04) compared with the placebo group. The mean plasma concentrations of 1′-hydroxymidazolam were lower in the propofol group than in the placebo group at 5, 10, 15, 20, and 30 minutes after midazolam was administered (P < .05). The mean (±SD) Michaelis-Menten constant for midazolam 1′-hydroxylation by human liver microsomes was 5.6 ± 3.3 μmol/L. The formation of 1′-hydroxymidazolam was competitively inhibited by propofol, and the mean inhibition constant was 56.7 ± 16.6 μmol/L. The mean Michaelis-Menten constant and mean inhibition constant values for midazolam 1′-hydroxylation by recombinant CYP3A4 were 4.0 μmol/L and 61.0 μmol/L, respectively, consistent with the mean values obtained from human liver microsomes. Conclusion: Propofol decreases the clearance of midazolam, and the possible mechanism is the competitive inhibition of hepatic CYP3A4. (Clin Pharmacol Ther 1999;66:110-7.) Naoya Hamaoka, MD, Yutaka Oda, MD, Ichiro Hase, MD, Koh Mizutani, MD, Tatsuo Nakamoto, MD, Takashi Ishizaki, MD, and Akira Asada, MD Osaka and Kumamoto, Japan From the Department of Anesthesiology and Intensive Care Medi- cine, Osaka City University Medical School, Osaka, and the Department of Pharmacology and Therapeutics, Graduate School of Clinical Pharmacy, Kumamoto University, Kumamoto. Supported in part by the Fund for Medical Research from Osaka City University Medical Research Foundation and a grant-in-aid for Research from the Ministry of Education, Science and Culture of Japan (No. 09771183). Received for publication Feb 17, 1999; accepted May 13, 1999. Reprint requests: Yutaka Oda, MD, Department of Anesthesiology and Intensive Care Medicine, Osaka City University Medical School, 1-5-7 Asahimachi, Abeno-ku, Osaka 545-8586, Japan. E- mail: m0987031@msic.med.osaka-cu.ac.jp Copyright © 1999 by Mosby, Inc. 0009-9236/99/$8.00 + 0 13/1/100038