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

  • Darrell R. Abernethy
    Correspondence
    Reprint requests: Darrell R. Abernethy, M.D., Ph.D., Division of Clinical Pharmacology, Box 1007, Tufts-New England Medical Center, 171 Harrison Avenue, Boston, Mass. 02111.
    Affiliations
    From the Division of Clinical Pharmacology, Departments of Psychiatry and Medicine, Tufts University School of Medicine and New England Medical Center, Boston, Mass. USA
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  • David J. Greenblatt
    Affiliations
    From the Division of Clinical Pharmacology, Departments of Psychiatry and Medicine, Tufts University School of Medicine and New England Medical Center, Boston, Mass. USA
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  • Marcia Divoll
    Affiliations
    From the Division of Clinical Pharmacology, Departments of Psychiatry and Medicine, Tufts University School of Medicine and New England Medical Center, Boston, Mass. USA
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  • Richard I. Shader
    Affiliations
    From the Division of Clinical Pharmacology, Departments of Psychiatry and Medicine, Tufts University School of Medicine and New England Medical Center, Boston, Mass. USA
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      Abstract

      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.

      Abbreviations:

      volume of distribution (Vd) (), ideal body weight (IBW) (), total body weight (TBW) (), uridine diphosphate (UDP) ()
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