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

Abstract

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 (t _1/2 a) averaged 24 min. Neither peak time nor t _1/2 a were influenced by age or sex. After a rapid phase of distribution, DMDZ elimination was slow, with a mean elimination half-life (t _1/2 β) of 82 h (range 27–219 h). t _1/2 β became prolonged with age in men but not in women Likewise, clearance of total (free plus bound) DMDZ declined with age in male subjects (r=−0.47, P<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<0.001). Partly due to a decline in plasma albumin with age (r=−0.47, P<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=−0.62, P<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.