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.
Jung
Hye Y
HY
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea.
Kang
Hee E
HE
Choi
Young H
YH
Kim
So H
SH
Lee
Myung G
MG
D058186:Acute Kidney Injury / Q000378:metabolism; D000818:Animals; D002753:Chlorzoxazone / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism*; D004195:Disease Models, Animal; D004347:Drug Interactions; D004731:Endotoxins / Q000494:pharmacology*; D007275:Injections, Intravenous; D007711:Klebsiella pneumoniae / Q000737:chemistry*; D008070:Lipopolysaccharides / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D009125:Muscle Relaxants, Central / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley
D004731:Endotoxins; D008070:Lipopolysaccharides; D009125:Muscle Relaxants, Central; C039289:6-hydroxychlorzoxazone; D019392:Cytochrome P-450 CYP2E1; D002753:Chlorzoxazone