Comparative pharmaceutical metabolism by rainbow trout (Oncorhynchus mykiss) liver S9 fractions
Comparative pharmaceutical metabolism by rainbow trout (Oncorhynchus mykiss) liver S9 fractions
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DOI：
10.1002/etc.2240
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发表时间：
2013-08-01
影响因子：
4.1
通讯作者：
Brooks, Bryan W.
中科院分区：
文献类型：
--
作者：
Connors, Kristin A.;Du, Bowen;Brooks, Bryan W.
药物在环境中的出现是一个日益令人关切的挑战。与许多工业化合物不同，药物在引入环境之前要经过广泛的测试。因此，原则上可以利用现有的药理学安全性数据，通过生物交叉读取方法来支持筛选级生物累积性环境风险评估。然而，很少有方法和强大的经验数据集存在，特别是比较药代动力学应用。对于许多药物，已在人体中鉴定出负责其代谢的主要细胞色素P450（CYP 450）酶。本研究的目的是采用比较的方法，以确定是否虹鳟鱼生物转化药物已知为特定的人类CYP的底物。根据CYP 3A 4、CYP 2D 6或CYP 2C 9在人体中的主要代谢选择了7种化合物。已知另外5种供试化合物是多种CYP的底物。使用底物耗竭法评价虹鳟鱼肝脏S9组分的代谢，该方法提供了固有肝清除率的估计值（CLIN VITRO，INT）。采用同位素稀释液相色谱-串联质谱法定量母体化学浓度。只有2种一般的底物表现出可测量的底物消耗水平。对于人CYP 2D 6、CYP 2C 9或CYP 3A 4的已知底物，未观察到显著的生物转化。这项研究的结果提供了新的信息，治疗鱼类模型可能代谢的基础上现有的哺乳动物数据。此外，这些结果表明，药物可能具有更大的倾向，生物积累在鱼比以前预期的。环境毒理化学2013;32：1810-1818。(c)2013年SETAC
The occurrence of pharmaceuticals in the environment presents a challenge of growing concern. In contrast to many industrial compounds, pharmaceuticals undergo extensive testing prior to their introduction to the environment. In principle, therefore, it may be possible to employ existing pharmacological safety data using biological read-across methods to support screening-level bioaccumulation environmental risk assessment. However, few approaches and robust empirical data sets exist, particularly for comparative pharmacokinetic applications. For many pharmaceuticals, the primary cytochrome P450 (CYP) enzymes responsible for their metabolism have been identified in humans. The purpose of the present study was to employ a comparative approach to determine whether rainbow trout biotransform pharmaceuticals known to be substrates for specific human CYPs. Seven compounds were selected based on their primary metabolism in humans by CYP3A4, CYP2D6, or CYP2C9. Five additional test compounds are known to be substrates for multiple CYPs. Metabolism by rainbow trout liver S9 fractions was evaluated using a substrate-depletion approach, which provided an estimate of intrinsic hepatic clearance (CLIN VITRO,INT). An isotope dilution liquid chromatography-tandem mass spectrometry method was employed for quantitation of parent chemical concentrations. Only 2 general CYP substrates demonstrated measurable levels of substrate depletion. No significant biotransformation was observed for known substrates of human CYP2D6, CYP2C9, or CYP3A4. The results of this study provide novel information for therapeutics that fish models are likely to metabolize based on existing mammalian data. Further, these results suggest that pharmaceuticals may possess a greater tendency to bioaccumulate in fish than previously anticipated. Environ Toxicol Chem 2013;32:1810-1818. (c) 2013 SETAC