Disposition of diazepam and its major metabolite desmethyldiazepam in patients with liver disease

Abstract

In six patients with cirrhosis and five patients with fibrosis of the liver elimination of diazepam (D) was compared after single and subchronic dosage. The pharmacokinetics of the major metabolite desmethyldiazepam (DD) was investigated infour healthy individuals and four patients with hepatic dysfunction and compared to its parent compound D. In the initial study, 11 patients with liver disease (cirrhosis and fibrosis) had a longer half-life (T_½(β)) of99.2 ± 23.2 hr after a single intravenous bolus of 0.1 mg/kg of D than to age-matched normal subjects (46.6 ± 14.2). After subchronic treatment with 10 mg of D for 7 days T_½(β) was prolonged only slightly (p = 0.043) in these patients (107.6 ± 25.1 hr). Neither total plasma clearance (Cl) nor the apparent volume of distribution (Vd_ss or Vd_Cl) showed significant changes. After intravenous injection of DD (0.1 mg/kg) plasma levels declined in the same biexponential manner as after D. The cross-over study in the four normal subjects demonstrated that DD was eliminated much more slowly than D. Whereas for D, T_½(β) and Cl were 32.6 ± 11.3 hr and 32.3 ± 11.0 ml/min, respectively, the corresponding values for DD were 50.9 ± 6.2 hr and 11.3 ± 3.1 ml/min. The accumulation (if DD after multiple dosage could be explained by the fact that it is formedfaster from D than it is eliminated. In four patients with liver disease the elimination (if D and the elimination (if DD were altered. In these patients T_½(β) for DD was prolonged (p = 0.015) to 108.2 ± 40.3 hr. This prolongation was caused by a decrease in Cl of 4.6 ± 1.1 ml/min, (p = 0.003) whereas Vd_(Cl) did not change significantly. This indicates that at least two steps in diazepam metabolism are impaired in patients with liver disease.