Pharmacokinetics of midazolam and its main metabolite 1-hydroxymidazolam in intensive care patients.
The pharmacokinetics of midazolam and of its main metabolite, 1-hydroxymidazolam, were investigated in intensive care patients after intravenous bolus of 0.2 mg/kg followed by a 0.1 mg/kg/h intravenous infusion of midazolam over 2 hours. A wide interpatient variability of the main pharmacokinetic parameters of midazolam was found. The mean values of elimination half life and volume of distribution, 4.5 +/- 5.4 h and 1.7 +/- 0.7 l/kg respectively, were higher than those reported in healthy subjects. Total plasma clearance was significantly increased in patients taking drugs that induce hepatic metabolism. Significant concentrations of the unconjugated form of 1-hydroxymidazolam were recovered in plasma. The volume of distribution and the elimination half life of the metabolite were higher than those of the parent drug. These results show that 1-hydroxymidazolam might contribute to the pharmacodynamic effect of midazolam and consequently must be taken into account during pharmacokinetic and pharmacodynamic studies.
Boulieu
R
R
Département de Pharmacie Clinique, de Pharmacocinétique et d' Evaluation du Médicament, Institut des Sciences Pharmaceutiques et Biologiques, Lyon, France.
Lehmann
B
B
Salord
F
F
Fisher
C
C
Morlet
D
D
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003422:Critical Care; D005260:Female; D006801:Humans; D006993:Hypnotics and Sedatives / Q000378:metabolism / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D008297:Male; D008874:Midazolam / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics*; D008875:Middle Aged
D006993:Hypnotics and Sedatives; C040081:1-hydroxymethylmidazolam; D008874:Midazolam