Chlorzoxazone metabolism is increased in fasted Sprague-Dawley rats

Abstract

Earlier data showed that men fasted for 38 h have a reduced rate of chlorzoxazone (CZ) metabolism suggesting a decreased level of cytochrome P450 2E1 (CYP2E1). In contrast, CYP2E1 level in fasted rats has been shown to be elevated. In this study, we investigated whether CZ metabolism in fasted rats was changed by determining the pharmacokinetics of CZ and its metabolite 6-hydroxyCZ (6-OHCZ), as a CYP2E1 probe, and by measuring liver CYP2E1 using immunoblot techniques. CZ was administered both by gavage (50 mg/kg) and by iv (25 mg/kg) to control (9 for oral and 3 for iv) and 24 h-fasted (9 for oral and 4 for iv) male Sprague-Dawley rats. Following sampling of blood through a jugular vein cannula, CZ and 6-OHCZ plasma concentrations were measured by HPLC with ultraviolet detection. Pharmacokinetic parameters for CZ 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 both CZ and 6-OHCZ was significantly increased in fasted rats in both the oral and iv study. A MANOVA covariance analysis and a multiple regression analysis revealed a significant correlation between 1/t ½ and CYP2E1 level and aniline hydroxylase activities. However, the correlations between 1/t ½ and pentoxyresorufin O-dealkylase, ethoxyresorufin Odealkylase and erythromycin N-demethylase were not significant. Therefore the contribution of other P450s to CZ metabolism seemed to be minor in the concentration range that we tested. In conclusion, fasting rats for 24 h causes a measurable induction of CYP2E1 that produces a significant increase in the rate of CZ metabolism and elimination. This is in contrast to the decreased metabolism of CZ reported for 38-hour fasted men (BJ prefers deletion of this sentence here but discussed in Discussion section?).

The Therapeutic Mode of Action of 4-Aminopyridine in Cerebellar Ataxia

“…In experiments performed in acutely prepared cerebellar slices we have recently determined the concentrations of CHZ that restores the precision of pacemaking in tottering Purkinje cells (Alviña and Khodakhah, under review). Moreover, using this information, and taking into account the pharmacokinetics of CHZ (Wan et al, 2006), we have found that supplementing the drinking water of the tottering mice with 15 mM CHZ markedly improves their performance on the rotarod (Alviña and Khodakhah, under review).…”

Toxicological implications of mitochondrial localization of CYP2E1

“…The induction of CYP2E1 has long been associated with fasting or starvation conditions 7, 8 . The fasting phenotype is characterized by high circulating ketone bodies, including acetone, acetoacetate, and beta-hydroxybutyrate, which would require a clearance mechanism to avoid toxicity.…”

KCaChannels as Therapeutic Targets in Episodic Ataxia Type-2

“…To achieve this we measured the daily water intake of the mice and found it to be ≈2.5 ml per day. We next took into consideration the fact that in rats, orally administered CHZ has a half-life of ≈60 min, and a single dose of 50 mg/kg results in a plasma concentration of ≈90 μM (oral half-life = 57.8±7.3 min (Wan et al, 2006). Based on this, we estimated that if the mice maintain their normal fluid intake replacement of their drinking water with one which contains ≈33 mM CHZ is likely to yield a plasma concentration of about 30 μM.…”