Effects of desmethyldiazepam on diazepam kinetics: a study of effects of a metabolite on parent drug disposition.

The effect of high concentrations of desmethyldiazepam (DMDZ), the major metabolite of diazepam (DZ), on parent drug kinetics was evaluated in six healthy young subjects who received a single intravenous dose (10 mg) of DZ on two occasions. The first DZ dose was given in the drug-free control condition and the second after the subject had ingested clorazepate (CZP), a precursor of DMDZ (15 mg daily for 7 days before DZ and then during the second DZ study). Maximum DMDZ concentration after the first DZ dose did not exceed 66 ng/ml, whereas mean DMDZ levels (derived from CZP) during the second DZ study were 481 +/- 61.5 ng/ml (SE) for all subjects. DZ kinetic parameters for all subjects during the first and second studies were: elimination half-life (t 1/2), 43.3 +/- 5.3 and 44.9 +/- 9.7 hr; total volume of distribution (Vd), 1.26 +/- 0.10 and 1.32 +/- 0.10 l/kg; unbound Vd, 97.4 +/- 9.9 and 94.9 +/- 9.9 l/kg; clearance, 0.364 +/- 0.048 and 0.394 +/- 0.055 ml/min/kg; and unbound clearance, 28.3 +/- 4.6 and 28.3 +/- 5.0 ml/min/kg. Percent unbound DZ was 1.40 +/- 0.25% when subject plasma was spiked with DZ alone and 1.47 +/- 0.21% when subjects' plasma was spiked with 500 ng/ml DMDZ in addition to DZ. Paired analysis of the two studies in each subject revealed no difference in t 1/2, Vd, unbound Vd, clearance, or DZ protein binding in the absence or presence of DMDZ. Formation and presence of the active metabolite DMDZ had no influence on kinetic behavior of parent DZ.