Time-dependent effects of Klebsiella pneumoniae endotoxin on the pharmacokinetics of chlorzoxazone and its main metabolite, 6- hydroxychlorzoxazone, in rats: Restoration of the parameters in 96 hour in KPLPS rats to control levels

Hye Y. Jung, Hee E. Kang, Young H. Choi, So H. Kim, Myung G. Lee

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1 Scopus citations

Abstract

It has been reported that chlorzoxazone (CZX) was primarily metabolized via hepatic Cyp2e1 to form 6-hydroxychlorzoxazone (OH-CZX) in rats, and the activity of aniline hydroxylase (a Cyp2e1 marker) in the liver was significantly decreased in rats at 24 h after pretreatment with lipopolysaccharide derived from Klebsiella pneumoniae (24 h KPLPS rats), whereas the levels were not changed at 2 h and 96 h in the KPLPS rats. Thus, the time-dependent pharmacokinetic parameters of CZX and OH-CZX were evaluated after the intravenous administration of CZX (20 mg/kg) to control rats, and the 2 h, 24 h and 96 h KPLPS rats along with the time-dependent changes in the protein expression of hepatic Cyp2e1. After the intravenous administration of CZX to 24 h KPLPS rats, the AUC0-2 h of OH-CZX and AUC OH-CZX, 0-2 h/AUCCZX were significantly smaller (by 40.5% and 71.2%, respectively) than those of controls due to the significant decrease (by 75.3%) in the protein expression of hepatic Cyp2e1. However, in 96 h KPLPS rats, the pharmacokinetic parameters of both CZX and OH-CZX were unchanged compared with controls due to the restoration of the protein expression of hepatic Cyp2e1 to control levels. These observations highlighted the existence of the time-dependent effects of KPLPS on the pharmacokinetics of CZX and OH-CZX in rats.

Original languageEnglish
Pages (from-to)485-493
Number of pages9
JournalBiopharmaceutics and Drug Disposition
Volume30
Issue number8
DOIs
StatePublished - 2009

Keywords

  • Chlorzoxazone and 6-hydroxychlorzoxazone
  • Hepatic Cyp2e1
  • Klebsiella pneumoniae
  • Pharmacokinetics
  • Rats

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