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 x kg(-1) IV for 1 minute followed by an infusion of 0.035 to 0.05 mg x kg(-1) x 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 microg x 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 microg x mL(-1), the plasma midazolam concentration was increased by 26.9% + or - 9.4% compared with midazolam given as a single drug. Propofol (C(blood): 1.2 microg x mL(-1)) reduced midazolam central volume of distribution from 5.37 to 2.98 L, elimination clearance from 0.39 to 0.31 L x min(-1), and rapid distribution clearance from 2.77 to 2.11 L x 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.
Lichtenbelt
Bart Jan
BJ
Department of Anesthesiology, University Medical Center, Groningen, University of Groningen, Groningen, The Netherlands.
Olofsen
Erik
E
Dahan
Albert
A
van Kleef
Jack W
JW
Struys
Michel M R F
MM
Vuyk
Jaap
J
D000328:Adult; D000465:Algorithms; D018686:Anesthetics, Intravenous / Q000097:blood / Q000494:pharmacology*; D003198:Computer Simulation; D018592:Cross-Over Studies; D004347:Drug Interactions; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D006801:Humans; D006993:Hypnotics and Sedatives / Q000097:blood / Q000493:pharmacokinetics*; D007262:Infusions, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D008874:Midazolam / Q000097:blood / Q000493:pharmacokinetics*; D015233:Models, Statistical; D017711:Nonlinear Dynamics; D015742:Propofol / Q000097:blood / Q000494:pharmacology*; D014018:Tissue Distribution
D018686:Anesthetics, Intravenous; D006993:Hypnotics and Sedatives; D008874:Midazolam; D015742:Propofol