Effects of cysteine on the pharmacokinetics of itraconazole in rats with protein‐calorie malnutrition
Effects of cysteine on the pharmacokinetics of itraconazole in rats with protein‐calorie malnutrition
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半胱氨酸对蛋白热量营养不良大鼠伊曲康唑药代动力学的影响
DOI：
10.1002/bdd.337
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发表时间：
2003
影响因子：
2.1
通讯作者：
M. Lee
中科院分区：
文献类型：
--
作者：
Ae;C. Ahn;E. J. Kim;J. Kwon;Sang G. Kim;S. Chung;C. Shim;M. Lee
研究了半胱氨酸对伊曲康唑药代动力学的影响，分别通过静脉给药（20 mg/kg）和口服给药（50 mg/kg）对伊曲康唑药代动力学的影响。对照组大鼠（23%酪蛋白饲粮）和PCM（蛋白质-热量营养不良，5%酪蛋白饲粮4周）和PCMC （PCM加口服半胱氨酸，250 mg/kg，第四周每天2次）。PCM大鼠静脉给予伊曲康唑后，伊曲康唑的血药浓度-时间曲线下面积（AUC）（3580µg min/ml比2670µg min/ml和2980µg min/ml）明显大于对照大鼠和PCMC大鼠（对照大鼠与PCMC大鼠之间无显著差异）。上述数据表明，伊曲康唑在PCM大鼠体内的代谢显著降低是由于抑制了大鼠肝微粒体细胞色素P450 (CYP) 3A23。结果是可以预料的，因为在PCM大鼠中，CYP3A23的水平与对照组相比显着下降。据报道，伊曲康唑在人体中通过CYP3A4代谢为几种代谢物，包括羟基伊曲康唑。人CYP3A4蛋白与大鼠CYP3A1 （CYP3A23）蛋白同源性为73%。通过补充半胱氨酸（PCMC大鼠），伊曲康唑的AUC完全恢复到对照水平。版权所有©2003 John Wiley & Sons， Ltd
The effects of cysteine on the pharmacokinetics of itraconazole were investigated after intravenous, 20 mg/kg, and oral, 50 mg/kg, administration of the drug to control rats (fed for 4 weeks on 23% casein diet) and rats with PCM (protein‐calorie malnutrition, fed for 4 weeks on 5% casein diet) and PCMC (PCM with oral cysteine supplementation, 250 mg/kg, twice daily during the fourth week). After intravenous administration of itraconazole to rats with PCM, the area under the plasma concentration–time curve from time zero to time infinity (AUC) of itraconazole was significantly greater (3580 compared with 2670 and 2980 µg min/ml) than those in control rats and rats with PCMC (the values between control rats and rats with PCMC were not significantly different). The above data suggested that metabolism of itraconazole decreased significantly in rats with PCM due to suppression of hepatic microsomal cytochrome P450 (CYP) 3A23 in the rats. The results could be expected since in rats with PCM, the level of CYP3A23 decreased significantly as compared to control. Itraconazole was reported to be metabolized via CYP3A4 to several metabolites, including hydroxyitraconazole, in human subjects. Human CYP3A4 and rat CYP3A1 (CYP3A23) proteins have 73% homology. By cysteine supplementation (rats with PCMC), the AUC of itraconazole was restored fully to control levels. Copyright © 2003 John Wiley & Sons, Ltd.