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Effects of cysteine on the pharmacokinetics of intravenous chlorzoxazone in rats with protein–calorie malnutrition
Author(s) -
Kim Yoon G.,
Cho Min K.,
Kwon Jong W.,
Kim Sang G.,
Chung Suk J.,
Shim ChangK.,
Lee Myung G.
Publication year - 2002
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/bdd.300
Subject(s) - chlorzoxazone , pharmacokinetics , chemistry , pharmacology , volume of distribution , cyp2e1 , urine , excretion , endocrinology , medicine , metabolism , biochemistry , cytochrome p450
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 μg min/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. Copyright © 2002 John Wiley & Sons, Ltd.