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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) ()To read this article in full you will need to make a payment
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References
- Principles of Drug Action: The Basis of Pharmacology.in: ed. 2. John Wiley & Sons, Inc.,, New York1974: 227-300
- Obesity, sex, and acetaminophen disposition.Clin Pharmacol Ther. 1982; 31: 783
- Alterations in drug distribution and clearance due to obesity.J Pharmacol Exp Ther. 1981; 217: 681
- Prolongation of drug half-life due to obesity: studies of desmethyldiazepam (Clorazepate).J Pharm Sci. 1982; 71: 942
- Clinical pharmacokinetics of lorazepam. I. Absorption and disposition of oral 14C-lorazepam.Clin Pharmacol Ther. 1976; 20: 329
- Clinical pharmacokinetics of oxazepam and lorazepam.Clin Pharmacokinet. 1981; 6: 89
- Weights of insured persons in the United States associated with lowest mortality.Stat Bull Metrop Life Insur Co. Nov–Dec, 1970; 40 (Anonymous)
- The use and interpretation of ponderal index and other weight-height ratios in epidemiological studies.J Chron Dis. 1970; 23: 93
- Analysis of lorazepam and its glucuronide metabolite by electron-capture gas-liquid chromatography. Use in pharmacokinetic studies of lorazepam.J. Chromatogr. 1978; 146: 311
- Effect of age and sex on lorazepam protein binding.J Pharm Pharmacol. 1982; 34: 122
- High pressure liquid chromatographic determination of acetaminophen in plasma: single-dose pharmacokinetic studies.J Chromatogr. 1981; 226: 224
- Fundamentals of Clinical Pharmacokinetics.Drug Intelligence Publications, Hamilton, Ill1975
- Clinical pharmacokinetics.N Engl J Med. 1975; 293: 702
- Clinical pharmacokinetics.N Engl J Med. 1975; 293: 964
- Absorption of oral and intramuscular chlordiazepoxide.Eur J Clin Pharmacol. 1978; 13: 267
- Pharmacokinetic comparison of sublingual lorazepam with intravenous, intramuscular, and oral lorazepam.J Pharm Sci. 1982; 71: 248
- Absolute bioavailability of oral and intramuscular diazepam: Effects of age and sex.Anesth Analg. 1983; 62: 1
- Theophylline disposition in obesity.Clin Pharmacol Ther. 1978; 23: 438
- Predicting in vivo benzodiazepine distribution based on in vitro lipophilicity.Clin Pharmacol Ther. 1982; 31: 200
- In vitro hepatic drug metabolism and microsomal enzyme induction in genetically obese rats.Biochem Pharmacol. 1980; 29: 289
- Fatty liver hepatitis and cirrhosis in obese patients.Am J Med. 1975; 67: 811
- A physiological approach to hepatic drug clearance.Clin Pharmacol Ther. 1975; 18: 377
- Pharmacokinetic evidence for the occurence of extrahepatic conjugative metabolism of p-nitrophenol in rats.Biochem Pharmacol. 1982; 31: 787
Article info
Publication history
Accepted:
January 11,
1983
Received:
October 26,
1982
Footnotes
☆Supported in part by grants AM-MH-32050 and MH-34223 from the United States Public Health Service.
Identification
Copyright
© 1983 Published by Elsevier Inc.
