Effect of age and sex on disposition of desmethyldiazepam formed from its precursor clorazepate

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Desmethyldiazepam (DMDZ) disposition was evaluated in 32 healthy male and female volunteers who ingested single 15-mg doses of the precursor compound, clorazepate dipotassium. DMDZ concentrations were measured in multiple plasma samples obtained between 7 and 9 days after dosage. Appearance of DMDZ in blood was rapid, with peak concentrations attained on average 1.5 h after dosage. Absorption half-life (t1/2 a) averaged 24 min. Neither peak time nor t1/2 a were influenced by age or sex. After a rapid phase of distribution, DMDZ elimination was slow, with a mean elimination half-life (t1/2 beta) of 82 h (range 27-219 h). t1/2 beta became prolonged with age in men but not in women. Likewise, clearance of total (free bound) DMDZ declined with age in male subjects (r=- 0.47, P less than 0.1), but was unrelated to age in women. DMDZ was extensively bound to protein in all subjects. The mean free fraction (FF) was 3.1% (range 2.0-4.3%), and increased significantly with declining plasma albumin concentrations (r=-0.57, P less than 0.001). Partly due to a decline in plasma albumin with age (r=-0.47, P less than 0.01), FF tended to increase with age (r=0.23). After correction for individual differences in FF, clearance of pharmacologically active unbound DMDZ declined significantly with age in men (r=-0.65, P less than 0.01), but actually was slightly higher in elderly as opposed to young women. Thus, the age-related decline in the capacity for hepatic hydroxylation of DMDZ is highly sex-specific.