Effects of cysteine on the pharmacokinetics of intravenous chlorzoxazone in rats with protein-calorie malnutrition.

Abstract

The effects of cysteine on the pharmacokinetics of chlorzoxazone (CZX) and one of its metabolites, 6-hydroxychlorzoxazone (OH-CZX), were investigated after intravenous administration of CZX, 25 mg/kg, to control rats (4-week fed on 23% casein diet) and rats with PCM (4-week fed on 5% casein diet) and PCMC (PCM with oral cysteine supplementation, 250 mg/kg, twice daily during the fourth week). In rats with PCM, the area under the plasma concentration-time curve from time zero to time infinity (AUC) of OH-CZX (436 compared with 972 microgmin/ml) and the percentages of intravenous dose of CZX excreted in 8-h urine as OH-CZX (20.2 compared with 38.5%) were significantly smaller than those in control rats. The above data indicated that the formation of OH-CZX from CZX decreased significantly in rats with PCM due to a significant decrease in chlorzoxazone-6-hydroxylase activity (328 compared with 895 pmol/min/mg protein) in the rats. The results were expected since in rats with PCM, hepatic CYP2E1 expression and its mRNA levels decreased significantly as compared to control, and CZX was metabolized to OH-CZX primarily by CYP2E1 in rats. By cysteine supplementation (rats with PCMC), some pharmacokinetic parameters restored fully (hepatic microsomal chlorzoxazone 6-hydroxylation activity based on both mg protein and nmol CYP450) or partially (total body clearance and apparent volume of distribution at steady state of CZX, and AUC, terminal half-life and 8-h urinary excretion of OH-CZX) to control levels.