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 less than 0.001) and
oxazepam (97 vs. 38 L, p less than 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 less than 0.005) and
oxazepam (157 vs. 50 ml/min, p less than 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 less than 0.01) and
oxazepam (r = 0.87, p less than 0.001), and clearance of LRZ and OXZ were similarly intercorrelated (r = 0.72, p less than 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.