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

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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.


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 Ct: 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.


In the presence of midazolam (Cblood: 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 (Cblood: 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.


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.

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