Prolonged Accumulation of Diazepam in Obesity

Six obese (mean weight 92 kg) and five normal (60 kg) subjects received 2 mg diazepam nightly for 30 nights. Determination of diazepam and desmethyldiazepam plasma concentrations during the dosing period and for a withdrawal period indicated that accumulation half‐life for both diazepam (7.8 days in obese vs. 3.1 days in normal subjects, P < 0.05) and desmethyldiazepam (30.3 vs. 7.2 days, P < 0.05) was markedly prolonged in obese subjects. However, mean steady‐state plasma concentrations of diazepam (68 vs. 67 ng/ml) and desmethyldiazepam (156 vs. 91 ng/ml) did not significantly differ between groups. To determine the basis for this delay in accumulation in obese subjects, single‐dose pharmacokinetics of diazepam and desmethyldiazepam were determined. Diazepam elimination half‐life was greatly prolonged in the obese subjects (82 vs. 32 hours, P < 0.005), with no change in total metabolic clearance (32 vs. 26 ml/min). Instead, a large increase in volume of distribution (228 vs. 70 liters, P < 0.01) was the reason for prolongation of the elimination half‐life. Similarly for desmethyldiazepam, elimination half‐life was prolonged in obese subjects (130 vs. 56 hours, P < 0.01), without a change in total metabolic clearance (13.7 vs. 19.2 ml/min), due to increased volume of distribution (151 vs. 73 liters, P < 0.01). During chronic dosing with diazepam, obese patients may experience a much slower onset of maximal drug effect compared to normal‐weight patients because of the greatly delayed accumulation of diazepam and desmethyldiazepam. After stopping diazepam administration, residual drug effect may likewise persist for a prolonged period in obese patients.