Evaluation of hepatic dysfunction in endotoxin pretreated rats using tolbutamide as a marker

Juzar S. Kaka, Khalil Al-Khamis, Musbah O M Tanira

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Abstract

The pharmacokinetics of tolbutamide (TB) have been studied in endotoxin pretreated rats with the aim of evaluating TB as a marker for endotoxin effects. Endotoxin dose of 10 mg/kg resulted in a 50% rate of mortality. TB was i.v. administered 24 h. after endotoxin dosing. Clearance (CI) decreased by approximately 2/3 of its value, area under the curve (AUC) and half-life (t1/2) in the pretreated animals were an average 1.5 times the values for the respective controls. Volume of distribution (Vd) increased by 10% approximately. These findings suggest that endotoxin pretreatment may cause hepatic damage by producing a decrease in Cl and an increase in the t1/2 of TB. But, SGOT levels in pretreated animals were no significantly different. This phenomenon may be explained by the increase in plasma protein binding of TB during endotoxin pretreatment, which decreases the free fraction of the drug in plasma available for metabolism. Endotoxin increased tmax of hydroxy-TB, while no change in Cmax was observed. Since tmax is inversely related to the formation and elimination rates of hydroxy-TB1 an increase in tmax may be due to the decrease in both elimination rates. No change in Cmax may be due to the decrease in the rate of formation which is equivalent to the decrease in the rate of elimination of hydroxy-TB.

Original languageEnglish
Pages (from-to)203-209
Number of pages7
JournalEuropean Journal of Drug Metabolism and Pharmacokinetics
Volume15
Issue number3
DOIs
Publication statusPublished - Jul 1990

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Keywords

  • endotoxin
  • hepatic dysfunction
  • rats
  • Tolbutamide

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Medicine(all)

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