[Clinical pharmacokinetics of diazepam and its biologically active metabolites (author's transl)]

Abstract

The pharmacokinetics of diazepam and its biologically active metabolites desmethyldiazepam and oxazepam is critically evaluated from a clinically relevant point of view. The slow elimination of diazepam is dependent on the degree of plasma protein binding, the duration of the medication, the age and the liver function of the patient. While the normal half-life (T1/2(beta)) varies between 1 and 2 days, it can be increased to up to 80--100 h in subjects over 60 years of age. In patients with liver disease T1/2(beta) is about doubled, which is caused by a reduction (factor 2) of the normal hepatic clearance of 26 ml/min. After subchronic treatment with diazepam the elimination rate is reduced about 20--70% in healthy subjects, but liver patients exhibit only a slightly further prolongation in T1/2(beta). The major metabolite desmethyldiazepam has a T1/2(beta) of 51 h and a Cl of 11 ml/min and accumulates after multiple doses of diazepam since its elimination is much slower than that of its parent compound. The elimination of this drug is also impaired (factor 2) in patients with liver disease. In contrast to these findings oxazepam is excreted as glucuronide in the urine relatively fast and independently of the liver function with a T1/2(beta) of 5.5 h and a Cl of 130 ml/min.