Propofol Reduces the Distribution and Clearance of Midazolam

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 C-T: 0.6 or 1.0 mu g . 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 mu g . mL(-1), the plasma midazolam concentration was increased by 26.9% +/- 9.4% compared with midazolam given as a single drug. Propofol (C-blood: 1.2 mu g . 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. (Anesth Analg 2010; 110: 1597 -606)Perioperative Medicine: Efficacy, Safety and Outcom