This study investigates the separate effects of age and hepatocellular liver disease on the disposition and elimination of diazepam (Valium) in man. It appears that the prolongation of the terminal plasma halflife (t 1/2 (β)) of diazepam with age is primarily dependent on an increase in the initial distribution volume of the drug. The plasma concentration/time course of the metabolite, desmethyldiazepam, was also affected by age. In older individuals, the initial presence and the peak values of desmethyldiazepam were observed later and the metabolite was present in lower concentrations. Despite the profound prolongation of t 1/2 (β) with age, the constancy of diazepam clearance indicates that drug plasma concentrations will not accumulate any more in the old than the young, and chronic dosage modifications based on pharmacokinetic considerations are unnecessary. The reduced clearance of diazepam in patients with acute and chronic parenchymal liver disease suggests that this drug should be used with caution, especially on a prolonged basis, in such individuals.
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