Effect of age and parenchymal liver disease on the disposition and elimination of chlordiazepoxide (librium).

There is an increased incidence of unwanted sedation associated with chlordiazepoxide usage in the elderly and in patients with liver disease. To determine whether pharmacokinetic alterations could account in part for these observations we studied the disposition and elimination of intravenously administered chlordiazepoxide in 27 healthy controls aged 16 to 86 years, 8 patients with cirrhosis, and 5 patients with acute viral hepatitis. Both increasing age and parenchymal liver disease led to similar changes in chlordiazepoxide pharmacokinetics. Over the age range 20 to 80 years, elimination half-life (t1/2(beta)) increased from 7 to 40 hr (r, 0.67; P less than 0.001) attributable to a decrease in plasma clearance from 30 ml per min to 10 ml per min (r, -0.71; P less than 0.001) and an increase in volume of distribution from 0.26 to 0.38 liters per kg (r, 0.60; P less than 0.05). Similarly, a decrease in plasma clearance in cirrhosis (7.7 +/- 2.1 compared to 15.3 +/- 4.4 ml per min, P less than 0.01) and acute viral hepatitis (6.1 +/- 4.3 compared to 18.1 +/- 7.1 ml per min, P less than 0.01) relative to age-matched controls and an increase in the volume of distribution resulted in a prolongation of the elimination half-life in both forms of liver disease. Impaired elimination of chlordiazepoxide may account in part for the increased incidence of oversedation seen in the elderly and in patients with liver disease.