Pharmacokinetics and Bioavailability of Intravenous, Intramuscular, and Oral Lorazepam in Humans

Abstract

Six healthy volunteers received single 2- and 4-mg doses of lorazepam by 5-min intravenous infusion, in tablet form by mouth in the fasting state, and by deltoid intramuscular injection in a six-way crossover study. A seventh subject received the 4-mg iv, po, and im doses. Concentrations of lorazepam and its glucuronide metabolite in multiple plasma samples and in all urine collected during 72 hr after each dose were determined by electron-capture GLC. Mean kinetic variables for intravenous lorazepam after 2- and 4-mg doses, respectively, were: volume of distribution (Vd), 1.14 and 1.30 liters/kg; elimination half-life (t1/2β), 14.3 and 14.6 hr; total clearance, 1.05 and 1.10 ml/min/kg; and cumulative urinary excretion of lorazepam glucuronide, 81.1 and 82.3% of the dose. With the possible exception of Vd, all kinetic variables were dose independent. Following a lag time averaging 15–17 min, absorption of oral lorazepam was first order, with apparent absorption half-life (t1/2α) values averaging 40 (2-mg dose) and 22 (4-mg dose) min. Absorption was 91–95% complete. No lag times were observed after intramuscular injection of lorazepam; absorption was first order, with t1/2a values averaging 12 (2-mg dose) and 19 (4-mg dose) min. The completeness of absorption was 83–100%. Absorption kinetics for both oral and intramuscular lorazepam were dose independent. Plasma t1/2β for intact lorazepam was independent of dose and administration route.