Pharmaceutical Metabolism in Fish: Using a 3-D Hepatic In Vitro Model to Assess Clearance.
Pharmaceutical Metabolism in Fish: Using a 3-D Hepatic In Vitro Model to Assess Clearance.
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DOI：
10.1371/journal.pone.0168837
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Jha AN
中科院分区：
文献类型：
--
作者：
Baron MG;Mintram KS;Owen SF;Hetheridge MJ;Moody AJ;Purcell WM;Jackson SK;Jha AN
在高内剂量下，药物有可能在鱼体内引起生物/药理学效应。对环境的一个特别关注是它们的生物积累和达到药理水平的潜力；因此，对这些对环境风险评价的影响的研究日益受到重视。为了避免不必要的动物实验，体外评估外源代谢的方法可以帮助进行生态毒理学评价。在这里，我们报告使用来自虹鳟鱼的3-D体外肝类器官培养系统（球体）来使用底物耗尽测定法测量七种药物的代谢。在测试的药物中，心得安、双氯芬酸和苯丁酮被鳟鱼肝脏球体代谢；阿替洛尔、美托洛尔、地西泮和卡马西平则没有。底物耗竭动力学数据被用于估算该球体模型的内在肝脏清除率，与双氯芬酸相似，与鳟鱼肝脏微粒体分数（S9）数据相比，心得安高约5倍。这些结果表明，肝球体可以作为一种相关的、具有代谢能力的体外模型，用于测量药物在鱼类体内的生物转化；心得安作为可重复的阳性对照。
At high internal doses, pharmaceuticals have the potential for inducing biological/pharmacological effects in fish. One particular concern for the environment is their potential to bioaccumulate and reach pharmacological levels; the study of these implications for environmental risk assessment has therefore gained increasing attention. To avoid unnecessary testing on animals, in vitro methods for assessment of xenobiotic metabolism could aid in the ecotoxicological evaluation. Here we report the use of a 3-D in vitro liver organoid culture system (spheroids) derived from rainbow trout to measure the metabolism of seven pharmaceuticals using a substrate depletion assay. Of the pharmaceuticals tested, propranolol, diclofenac and phenylbutazone were metabolised by trout liver spheroids; atenolol, metoprolol, diazepam and carbamazepine were not. Substrate depletion kinetics data was used to estimate intrinsic hepatic clearance by this spheroid model, which was similar for diclofenac and approximately 5 fold higher for propranolol when compared to trout liver microsomal fraction (S9) data. These results suggest that liver spheroids could be used as a relevant and metabolically competent in vitro model with which to measure the biotransformation of pharmaceuticals in fish; and propranolol acts as a reproducible positive control.
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影响因子：
16.6
作者：
Berthelot, Camille;Brunet, Frederic;Chalopin, Domitille;Juanchich, Amelie;Bernard, Maria;Noel, Benjamin;Bento, Pascal;Da Silva, Corinne;Labadie, Karine;Alberti, Adriana;Aury, Jean-Marc;Louis, Alexandra;Dehais, Patrice;Bardou, Philippe;Montfort, Jerome;Klopp, Christophe;Cabau, Cedric;Gaspin, Christine;Thorgaard, Gary H.;Boussaha, Mekki;Quillet, Edwige;Guyomard, Rene;Galiana, Delphine;Bobe, Julien;Volff, Jean-Nicolas;Genet, Carine;Wincker, Patrick;Jaillon, Olivier;Roest Crollius, Hugues;Guiguen, Yann
通讯作者：
Guiguen, Yann
影响因子：
11.4
作者：
Kallio, Jenny-Maria;Lahti, Marja;Kronberg, Leif
通讯作者：
Kronberg, Leif
影响因子：
4.1
作者：
Connors, Kristin A.;Du, Bowen;Brooks, Bryan W.
通讯作者：
Brooks, Bryan W.
影响因子：
4.5
作者：
Benet, Leslie Z.;Broccatelli, Fabio;Oprea, Tudor I.
通讯作者：
Oprea, Tudor I.
影响因子：
56.9
作者：
Brodin, T.;Fick, J.;Klaminder, J.
通讯作者：
Klaminder, J.