Induction of glutathione synthesis explains pharmacodynamics of high-dose busulfan in mice and highlights putative mechanisms of drug interaction
Induction of glutathione synthesis explains pharmacodynamics of high-dose busulfan in mice and highlights putative mechanisms of drug interaction
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DOI：
10.1124/dmd.106.012880
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发表时间：
2007-02-01
影响因子：
3.9
通讯作者：
Vassal, Gilles
中科院分区：
文献类型：
--
作者：
Bouligand, Jerome;Deroussent, Alain;Vassal, Gilles
白消安是通过谷胱甘肽S-转移酶（GST）催化与还原型谷胱甘肽（GSH）结合消除的药物的一个例子。我们研究了白消安在C57 BL 6小鼠的药代动力学和毒性与肝脏GST活性和GSH合成的前体，即γ-谷氨酰半胱氨酸和半胱氨酸的准确测定。与每天一次接受33 mg/kg白消安的动物相比，每天两次接受16.5 mg/kg白消安的小鼠中观察到的急性毒性发生率显著降低。在这两种情况下，在4天内给予的总剂量为132 mg/kg。毒性差异可通过药代动力学解释，因为仅在每日两次给药的动物中观察到强烈的清除诱导。代谢诱导与肝脏半胱氨酸含量的增加和谷胱甘肽合成率的提高相关，而GST活性不变。据我们所知，这是第一次在体内GSH合成通量已被证明是密切相关的药物血浆清除率和毒性。这些结果允许假设GSH肝脏合成可能直接影响白消安清除在人类肝静脉闭塞性疾病的发生可能的影响。
Busulfan is an example of a drug eliminated through glutathione S-transferase (GST)-catalyzed conjugation with reduced glutathione (GSH). We studied the pharmacokinetics and toxicity of busulfan in C57BL6 mice in correlation with liver GST activity and GSH synthesis by accurate determination of precursors, namely, gamma-glutamylcysteine and cysteine. A significantly lower incidence of acute toxicity was observed in mice receiving busulfan 16.5 mg/kg twice a day compared with animals receiving 33 mg/kg once a day. In both cases, a total dose of 132 mg/kg was administered over 4 days. The difference in toxicity was explained by pharmacokinetics since a strong induction of clearance was observed only in animals treated twice daily. Induction of metabolism was correlated with an increase in liver cysteine content and enhanced glutathione synthesis rate, whereas GST activity was unchanged. To our knowledge, this is the first time that in vivo flux of GSH synthesis has been shown to be closely related to a drug plasma clearance and toxicity. These results allow hypothesizing that GSH liver synthesis may directly influence busulfan clearance in humans with possible implications in the occurrence of hepatic veno-occlusive disease.