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ANESTHETIC PHARMACOLOGY

Mixed-Effects Modeling of the Influence of Midazolam on Propofol Pharmacokinetics

Jaap Vuyk, MD, PhD^*, Bart Jan Lichtenbelt, MD, Erik Olofsen, MSc^*, Jack W. van Kleef, MD, PhD^*, and Albert Dahan, MD, PhD^*

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

Address correspondence to Jaap Vuyk, MD, PhD, Department of Anesthesiology, Leiden University Medical Center, PO Box 9600, 2333 ZA, Leiden, The Netherlands. Address e-mail to j.vuyk{at}lumc.nl.

BACKGROUND: The combined administration of anesthetics has been associated with pharmacokinetic interactions that induce concentration changes of up to 30%. Midazolam is often used as a preoperative sedative in advance of a propofol-based anesthetic. In this study, we identified the influence of midazolam on the pharmacokinetics of propofol.

METHODS: Eight healthy male volunteers were studied on two occasions in a random crossover manner. During Session A, volunteers received propofol 1 mg/kg in 1 min followed by an infusion of 2.5 mg · kg^–1 · h^–1 for 59 min. During Session B, in addition to this propofol infusion scheme, a target-controlled infusion of midazolam (constant C_t: 125 ng/mL) was given from 15 min before the start until 6 h after termination of the propofol infusion. Arterial blood samples for blood propofol and plasma midazolam concentration analysis were taken until 6 h after termination of the propofol infusion. Nonlinear mixed-effects models examining the influence of midazolam and hemodynamic variables on propofol pharmacokinetics were constructed using Akaike criterion for model selection.

RESULTS: In the presence of midazolam (C_blood: 224.8 ± 41.6 ng/mL), the blood propofol concentration increased by 25.1% ± 13.3% compared with when propofol was given as single drug. Midazolam (C_blood: 225 ng/mL) reduced propofol Cl₁ from 1.94 to 1.61 L/min, Cl₂ from 2.86 to 1.52 L/min, and Cl₃ from 0.95 to 0.73 L/min. Inclusion of mean arterial blood pressure further improved the propofol pharmacokinetic model.

CONCLUSIONS: Midazolam reduces the metabolic and rapid and slow distribution clearances of propofol. In addition, a reduction in mean arterial blood pressure is associated with propofol pharmacokinetic alterations that increase the blood propofol concentration.