Chlorzoxazone metabolism is increased in fasted Sprague-Dawley rats.
Earlier data showed that men fasted for 38 h had a reduced rate of chlorzoxazone metabolism, suggesting a decreased level of cytochrome P450 2E1 (CYP2E1). In contrast, the level of CYP2E1 in fasted rats had been shown to be elevated. In this study, we have investigated whether chlorzoxazone metabolism in fasted rats was changed by determining the pharmacokinetics of chlorzoxazone and its metabolite, 6-hydroxychlorzoxazone (6-OHCZ), as a CYP2E1 probe, and by measuring liver CYP2E1 using immunoblot techniques. Chlorzoxazone was administered by gavage (50 mg kg(-1)) or intravenously (25 mg kg(-1)) to control (nine for oral and three for intravenous) and 24 h-fasted (nine for oral and four for intravenous) male Sprague-Dawley rats. Following sampling of blood through a jugular vein cannula, chlorzoxazone and 6-OHCZ plasma concentrations were measured by HPLC with UV detection. Pharmacokinetic parameters for chlorzoxazone and 6-OHCZ in each treatment group were determined by model fitting and non-compartmental analysis. In parallel with the increased liver CYP2E1 level, the elimination of chlorzoxazone and 6-OHCZ was significantly increased in fasted rats in the oral and the intravenous study. A multiple analysis of variance covariance analysis and a multiple regression analysis revealed a significant correlation between 1/t(1/2) and CYP2E1 level and aniline hydroxylase activity. However, the correlation between 1/t(1/2) and pentoxyresorufin O-dealkylase, ethoxyresorufin O-dealkylase and erythromycin N-demethylase was not significant. Therefore the contribution of other P450s to chlorzoxazone metabolism seemed to be minor in the concentration range that we tested. In conclusion, fasting rats for 24 h caused a measurable induction of CYP2E1, which produced a significant increase in the rate of chlorzoxazone metabolism and elimination.
Wan
Jie
J
Laboratory of Clinical Studies, NIAAA, NIH, Bethesda, MD 20892-1256, USA. jwan2@yahoo.com
Ernstgård
Lena
L
Song
Byoung J
BJ
Shoaf
Susan E
SE
D000284:Administration, Oral; D000815:Aniline Hydroxylase / Q000378:metabolism; D000818:Animals; D002753:Chlorzoxazone / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D019362:Cytochrome P-450 CYP2B1 / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000096:biosynthesis*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D005215:Fasting / Q000378:metabolism*; D018565:Food-Drug Interactions; D007275:Injections, Intravenous; D008099:Liver / Q000201:enzymology; D008297:Male; D009125:Muscle Relaxants, Central / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley
D009125:Muscle Relaxants, Central; D019392:Cytochrome P-450 CYP2E1; D000815:Aniline Hydroxylase; D019363:Cytochrome P-450 CYP1A1; D019362:Cytochrome P-450 CYP2B1; D051544:Cytochrome P-450 CYP3A; D002753:Chlorzoxazone