Enhanced glucuronide conjugation of drugs in obesity: studies of lorazepam, oxazepam, and acetaminophen

The influence of obesity on the distribution or clearance of lorazepam and oxazepam, two benzodiazepines biotransformed by glucuronide conjugation, was studied in a series of obese subjects (mean weight 113 kg; mean percent IBW 179%) and healthy controls of normal body habitus matched for age and sex. Overweight subjects and controls received 2 to 3 mg of lorazepam intravenously or 30 mg of oxazepam orally. Absolute Vd in obese compared to control subjects was increased for both lorazepam (131 vs. 77 L, p < 0.001) and oxazepam (97 vs. 38 L, p < 0.001). When normalized to body weight, Vd/kg was similar for both drugs. Total metabolic clearance was similarly increased in the obese cohort for lorazepam (102 vs. 63 ml/min, p < 0.005) and oxazepam (157 vs. 50 ml/min, p < 0.001). Again, when normalized to body weight, clearance per kilogram was similar for both drugs. Since both Vd and clearance increased with body weight, elimination half-life (dependent on both Vd and clearance) was not significantly different in obese subjects (lorazepam 16.5 vs. 14.9 hr; oxazepam 7.7 vs. 8.9 hr). A random subgroup of obese and control subjects received a single intravenous dose of acetaminophen, also biotransformed by conjugation. Acetaminophen clearance was significantly correlated with that of lorazepam (r = 0.59, p < 0.01) and oxazepam (r = 0.87, p < 0.001), and clearance of LRZ and OXZ were similarly intercorrelated (r = 0.72, p < 0.01). Thus obesity is associated with enhanced capacity for biotransformation of drugs via glucuronide conjugation, conjugating capacity increases in proportion to TBW and is consistent among drugs biotransformed by this mechanism.