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Propofol Reduces the Distribution and Clearance of Midazolam

Lichtenbelt, Bart Jan MD*; Olofsen, Erik MSc; Dahan, Albert MD, PhD; van Kleef, Jack W. MD, PhD; Struys, Michel M. MD, PhD*; Vuyk, Jaap MD, PhD

doi: 10.1213/ANE.0b013e3181da91bb
Anesthetic Pharmacology: Research Reports

BACKGROUND: Midazolam, at sedative levels, increases blood propofol concentrations by 25%. We evaluated the reverse interaction and determined the influence of propofol on the pharmacokinetics of midazolam.

METHODS: Eight healthy male volunteers were studied on 2 occasions in a random crossover manner. During session A, volunteers received midazolam 0.035 to 0.05 mg · kg−1 IV for 1 minute followed by an infusion of 0.035 to 0.05 mg · kg−1 · h−1 for 59 minutes. During session B, in addition to this midazolam infusion scheme, a target-controlled infusion of propofol (constant CT: 0.6 or 1.0 μg · mL−1) was given from 15 minutes before the start until 6 hours after termination of the midazolam infusion. Arterial blood samples for propofol and midazolam concentration analysis were taken until 6 hours after termination of the midazolam infusion. Nonlinear mixed-effect models examining the influence of propofol and hemodynamic variables on midazolam pharmacokinetics were constructed using Akaike's information-theoretic criterion for model selection.

RESULTS: In the presence of a mean blood propofol concentration of 1.2 μg · mL−1, the plasma midazolam concentration was increased by 26.9% ± 9.4% compared with midazolam given as a single drug. Propofol (Cblood: 1.2 μg · mL−1) reduced midazolam central volume of distribution from 5.37 to 2.98 L, elimination clearance from 0.39 to 0.31 L · min−1, and rapid distribution clearance from 2.77 to 2.11 L · min−1. Inclusion of heart rate further improved the pharmacokinetic model of midazolam.

CONCLUSIONS: Propofol reduces the distribution and clearance of midazolam in a concentration-dependent manner. In addition, inclusion of heart rate as a covariate improved the pharmacokinetic model of midazolam predominantly through a reduction in the intraindividual variability.

Published ahead of print April 30, 2010

From the *Department of Anesthesiology, University Medical Center Groningen, University of Groningen, Groningen; and Department of Anesthesiology, Leiden University Medical Center (LUMC), Leiden, The Netherlands.

Supported by the Department of Anesthesiology, Leiden University Medical Centre, Leiden, The Netherlands.

Presented at the Annual Meeting of the American Society of Anesthesiologists, Chicago, October 14–18, 2006 (Abstract no. 839).

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (

Address correspondence and reprint requests to Jaap Vuyk, MD, PhD, Department of Anesthesiology, Leiden University Medical Center, PO Box 9600, 2300 RC, Leiden, The Netherlands. Address e-mail to

Accepted February 12, 2010

Published ahead of print April 30, 2010

© 2010 International Anesthesia Research Society
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