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.