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 less than 0.05) and desmethyldiazepam (30.3 vs. 7.2 days, P less than 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 less than 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 less than 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 less than 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 less than 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.(ABSTRACT TRUNCATED AT 250 WORDS)
D000328:Adult; D003009:Clorazepate Dipotassium / Q000008:administration & dosage / Q000097:blood; D003975:Diazepam / Q000008:administration & dosage* / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006801:Humans; D007700:Kinetics; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D003708:Nordazepam / Q000097:blood; D009765:Obesity / Q000378:metabolism*
D003009:Clorazepate Dipotassium; D003708:Nordazepam; D003975:Diazepam