Mixed-effects modeling of the influence of midazolam on propofol pharmacokinetics.
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 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.


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 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.


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.
Vuyk
Jaap
J
Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands. j.vuyk@lumc.nl
Lichtenbelt
Bart Jan
BJ
Olofsen
Erik
E
van Kleef
Jack W
JW
Dahan
Albert
A
D000328:Adult; D018686:Anesthetics, Intravenous / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001711:Biotransformation / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D003198:Computer Simulation; D018592:Cross-Over Studies; D004334:Drug Administration Schedule; D004347:Drug Interactions; D006801:Humans; D006993:Hypnotics and Sedatives / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D007262:Infusions, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D008874:Midazolam / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D008954:Models, Biological; D017711:Nonlinear Dynamics; D015742:Propofol / Q000008:administration & dosage / Q000493:pharmacokinetics*; D055815:Young Adult
D018686:Anesthetics, Intravenous; D006993:Hypnotics and Sedatives; D008874:Midazolam; D015742:Propofol