[Important factors determining human distribution and elimination of diazepam]

The pharmacokinetics of diazepam and its biologically active major metabolite desmethyldiazepam were investigated under clinically relevant situations. Both drugs were measured in the different specimens (blood, plasma, urine, bile) by a specific and sensitive gas-liquid chromatographic assay. The pharmacokinetic data were analyzed by the digital computer program SAAM-25 according to the two compartment open model. In healthy subjects the elimination half-life (T1/2(beta))is dependent on the age of the individuals, which is caused by changes in the apparent volume of distribution. The strong plasma protein binding of 95 to 98 percent determines the low hepatic clearance of diazepam. Only neglible amounts of a dose are excreted unchanged with the bile and into the urine. After multiple dosing with diazepam its T1/2(beta) is prolonged, which is caused by a lowered clearance. Thereby also desmethyldiazepam accumulates, since it is eliminated about three times slower than its parent compound. In patients with dysfunction of the liver (cirrhosis, hepatitis) diazepam and desmethyldiazepam exhibit a prolonged T1/2(beta) and a reduced clearance and the lowered plasma protein binding causes a larger volume of distribution. Animal and in vitro experiments demonstrate, besides species dependent differences, that the elimination of diazepam can be impaired by the accumulating desmethyldiazepam.