Effects of aging and liver disease on disposition of lorazepam.

Abstract

The disposition of lorazepam after intravenous administration (2 mg) was investigated in patients with alcoholic cirrhosis and acute viral hepatitis, and compared to that in normal subjects ranging in age from 15 to 73 yr. No statistically significant age‐dependent relationships in the drug's pharmacokinetic parameters were observed. Cirrhosis was associated with a doubling of the mean elimination half‐life (21.7 ± 7.6 to 41.2 ± 24.5 hr). This was due to a similar increase in the volume of distribution of lorazepam, caused by a reduction in the extent of the drug's plasma binding (88.6 ± 2.5 from 93.2 ± 1.8). No changes in systemic plasma clearance of either the unbound (about 11 ml/min/kg) or bound plus unbound (about 0.75 ml/min/kg) lorazepam, or urinary recovery of conjugated drug (about 50%) were detected. In contrast, there were no significant changes in the kinetics of lorazepam in the patients with acute viral hepatitis. Comparison of lorazepam's systemic plasma clearance in the liver disease patients in whom studies with antipyrine and chlordiazepoxide had also been performed indicated impairment in their values but this was not the case for lorazepam. It is concluded that the degree of impairment, if any, in the metabolism of lorazepam in patients with liver disease is considerably less than that of certain other drugs including related benzodiazepines. Aging also does not lead to alterations either in distribution or metabolism as have been observed with other benzodiazepines. It is speculated that these observations may reflect characteristics of the drugs associated with their metabolic fate, i.e., glucuronidation or oxidative biotransformation.