Prolongation of Drug Half-Life due to Obesity: Studies of Desmethyldiazepam (Clorazepate)

Abstract

Desmethyldiazepam pharmacokinetics were determined after oral administration of its precursor, clorazepate, to 12 obese subjects (mean weight: 105.4 kg; mean percent ideal body weight: 170%) who were matched for age, sex, and smoking habits with 12 normal controls (66.5 kg; percent ideal body weight: 103.3%). After an overnight fast, a single 15-mg clorazepate capsule, equivalent to 10.3 mg of desmethyldiazepam, was administered. Multiple plasma samples drawn 10–42 days postdose were analyzed for desmethyldiazepam by electron-capture GLC. Obese subjects compared to controls had a prolonged desmethyldiazepam elimination half-life (t1/2) (154.1 hr versus 57.1 hr; p < 0.005). Assuming quantitative conversion of clorazepate to desmethyldiazepam and 100% systemic availability, volume of distribution (Vd ) was greatly increased in the obese (158.8 liters versus 63.3 liters; p < 0.001). The value of Vd remained greater even after correction for body weight (1.52 liter/kg versus 0.94 liter/kg; p < 0.005). However, clearance of desmethyldiazepam was not different between groups (13.2 ml/min in obese versus 13.4 ml/min in controls). The percent ideal body weight was highly correlated with Vd (r = 0.82), as was total body weight (r = 0.86). The value of t1/2 was correlated highly with Vd (r = 0.89) but only weakly with clearance (r = —0.38). Therefore, the large increase in the desmethyldiazepam t1/2 value seen in obese subjects is predominantly due to the disproportionate distribution of this lipid-soluble drug into body fat as opposed to lean tissue. The contribution of clearance to desmethyldiazepam t1/2 was of much less importance than was Vd in this obese study population.