Pharmacokinetics and bioavailability of intravenous and intramuscular lorazepam with an adjunct test of the inattention effect in humans

Abstract

Single dose pharmacokinetics and bioavailability of intravenous and intramuscular lorazepam were investigated in 6 younger healthy human volunteers of either sex. The plasma concentration profile after intravenously administered lorazepam could in all cases be fitted by NONLIN to a biexponential function of time with a mean terminal (biological) half-life of 14.10 hrs +/- 2.94 S.D. (range 9.68 - 18.42 hrs). The mean half-life of the initial alpha-phase of distribution was 0.31 hrs +/- 0.11 S.D. The mean apparent volume of distribution derived from AUC, Vd-area (=Vd beta), was 1.24 1 kg-1 +/- 0.17 S.D. Mean plasma clearance of the drug was 62.17 ml kg-1 hr-1 +/- 8.85 S.D. The apparent central volume of distribution characterizing the open two-compartment pharmacokinetic model was 0.59 1 kg-1 +/- 0.19 S.D. After intramuscular administration to the same subjects the plasma concentration time lapse could be described by either tri- or bi-exponential kinetics, which are representative of open two- and one-compartment models with absorption phases, respectively. Mean biological half-life was 14.01 hrs +/- 2.31 S.D. and Vd-area 1.24 l kg-1 +/- 0.14 S.D., both values in full agreement with the findings based on intravenous administration. Half-life of the absorption phase varied from 0.08 to 1.76 hrs. Mean systemic availability of the drug was 88.8% +/- 8.3 S.D. The inattention effect of lorazepam was assessed by exposing the subjects during the intravenous pharmacokinetic experiments to a binaural stimulation test, which revealed various degrees of acute reduced attention in only three of the subjects.