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

Abstract

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 x kg(-1) x 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. 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 Cl(1) from 1.94 to 1.61 L/min, Cl(2) from 2.86 to 1.52 L/min, and Cl(3) 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.