Department of Environmental Science, Baylor University, Waco, Texas; Center for Reservoir and Aquatic Systems Research, Baylor University, Waco, Texas; Institute of Biomedical Studies, Baylor University, Waco, Texas.
Chirality. 2013 Nov;25(11):763-7. doi: 10.1002/chir.22211. Epub 2013 Jul 29.
The occurrence of pharmaceuticals in the environment represents a challenge of emerging concern. Many pharmaceuticals are chiral compounds; however, few studies have examined the relative toxicity of pharmaceutical enantiomers to wildlife. Further, our understanding of stereospecific pharmacokinetics remains largely informed by research on humans and a few well-studied laboratory test animals, and not by studies conducted with environmentally relevant species, including fish. The objective of this study was to investigate whether rainbow trout display stereospecific in vitro metabolism of three common chiral pharmaceuticals. Metabolism by trout liver S9 fractions was evaluated using a substrate depletion approach, which provides an estimate of intrinsic hepatic clearance (CL(IN VITRO,INT)). No biotransformation was observed for rac-, R-, or S-fluoxetine. Ibuprofen, including both enantiomers and the racemic mixture, appeared to undergo slow metabolism, but the resulting substrate depletion curves did not differ significantly from those of inactive controls. Contrary to relative clearance rates in humans, S(-)-propranolol was more rapidly cleared than the R(+)-enantiomer. This work demonstrates that relative clearance rates and the effects of racemic mixtures in trout could not have been predicted based on human data. Additional research describing species differences and exploring tools for species extrapolation in biomedical and environmental studies is needed.
环境中药物的存在是一个新出现的问题。许多药物都是手性化合物；然而，很少有研究考察药物对野生动物对映体的相对毒性。此外，我们对手性药物立体选择性药代动力学的理解在很大程度上仍然依赖于对人类和一些经过充分研究的实验室试验动物的研究，而不是对包括鱼类在内的具有环境相关性的物种进行的研究。本研究的目的是考察虹鳟鱼是否表现出三种常见手性药物的体外立体选择性代谢。采用底物耗竭法评价了鱼肝 S9 级分的代谢情况，该方法可提供内在肝清除率（CL（体外，INT））的估计值。rac-、R-和 S-氟西汀均未观察到生物转化。布洛芬，包括两种对映体和外消旋混合物，似乎经历了缓慢的代谢，但所得的底物耗竭曲线与无活性对照物没有显著差异。与人类的相对清除率相反，S(-)-普萘洛尔比 R(+)-对映体清除得更快。这项工作表明，根据人类数据，无法预测相对清除率和混合物对鱼类的影响。需要进一步研究描述物种差异，并探索在生物医学和环境研究中进行物种外推的工具。
