Prolongation of drug half‐life due to obesity: Studies of desmethyldiazepam (clorazepate)

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 (t_1/2) (154.1 hr versus 57.1 hr;p < 0.005). Assuming quantitative conversion of clorazepate to desmethyldiazepam and 100% systemic availability, volume of distribution (V_d) was greatly increased in the obese (158.8 liters versus 63.3 liters; p < 0.001). The value of V_d 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 V_d (r = 0.82), as was total body weight (r = 0.86). The value of t_1/2 was correlated highly with V_d (r = 0.89) but only weakly with clearance (r = ‐0.38). Therefore, the large increase in the desmethyldiazepam t_1/2 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 t_1/2 was of much less importance than was V_d in this obese study population.