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

1979; Elsevier BV; Volume: 68; Issue: 1 Linguagem: Inglês

10.1002/jps.2600680119

1520-6017

David J. Greenblatt, Richard I. Shader, Käte Franke, Dean S. MacLaughlin, Jerold S. Harmatz, Marcia D. Allen, Ann Werner, Elaine Woo,

Neurotransmitter Receptor Influence on Behavior

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.