PHARMACOKINETICS OF MIDAZOLAM AND ITS MAIN METABOLITE 1-HYDROXYMIDAZOLAM IN INTENSIVE-CARE PATIENTS

The pharmacokinetics of midazolam and of its main metabolite, 1-hydrox ymidazolam, were investigated in intensive care patients after intrave nous 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 mai n pharmacokinetic parameters of midazolam was found. The mean values o f 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 heal thy subjects. Total plasma clearance was significantly increased in pa tients taking drugs that induce hepatic metabolism. Significant concen trations of the unconjugated form of 1-hydroxymidazolam were recovered in plasma. The volume of distribution and the elimination half life o f the metabolite were higher than those of the parent drug. These resu lts show that 1-hydroxymidazolam might contribute to the pharmacodynam ic effect of midazolam and consequently must be taken into account dur ing pharmacokinetic and pharmacodynamic studies.