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

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 AUC_{0–2 h} of OH‐CZX and AUC_{OH‐CZX, 0–2 h}/AUC_CZX 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. Copyright © 2009 John Wiley & Sons, Ltd.