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Comparative in vitro hepatic clearances of commonly used antidepressants, antipsychotics, and anti-inflammatory agents in rainbow trout liver S9 fractions
Aquatic Toxicology ( IF 4.1 ) Pub Date : 2024-08-11 , DOI: 10.1016/j.aquatox.2024.107048
Tea L M Pihlaja 1 , Jade Pätsi 2 , Elisa Ollikainen 2 , Tiina M Sikanen 1
Affiliation  

Residues of human pharmaceuticals are widely detected in surface waters and can be taken up by and bioaccumulate in aquatic organisms, especially fish. One of the key challenges in assessing the bioaccumulation potential of ionizable organic compounds, such as the pharmaceuticals, is the lack of empirical data for biotransformation. In the present study, we assessed the in vitro intrinsic clearances (CL) of twelve pharmaceuticals, individually and some additionally as mixtures, in rainbow trout () liver S9 fractions (RT-S9) adhering to the OECD test guidance 319B. The test substances included four anti-inflammatory agents (diclofenac, ibuprofen, ketoprofen, naproxen), seven antidepressants/antipsychotics (citalopram, haloperidol, levomepromazine, mirtazapine, risperidone, sertraline, venlafaxine) and the O-desmethyl metabolite of venlafaxine. Quantifiable intrinsic clearances were detected for diclofenac, ibuprofen, naproxen, levomepromazine, and sertraline. Apart from diclofenac, the in vitro clearances of the other four pharmaceuticals were shown to be critically dependent on the cytochrome P450 (CYP) metabolism. Therefore, we also determined the half-maximal inhibitory concentrations (IC) of the same twelve pharmaceuticals toward CYP1A-like (7-ethoxyresorufin-O-deethylation, EROD) and CYP3A-like (benzyloxy-4-trifluoromethylcoumarin-O-debenzyloxylation, BFCOD) activities in RT-S9 using IC shift assay. As a result, levomepromazine and sertraline were identified as the most potent inhibitors of both EROD and BFCOD activity (unbound IC < 10 µM each), followed by citalopram and haloperidol (10 µM < IC < 100 µM). Additionally, mirtazapine was a selective EROD inhibitor (IC ∼ 30 µM). The inhibitory impacts of haloperidol and sertraline were indicatively time dependent. Finally, we carried out intrinsic clearance assays with mixtures of diclofenac, ibuprofen, naproxen, levomepromazine, and sertraline to examine the impacts of EROD and BFCOD inhibitions on their in vitro CL in RT-S9. Our in vitro data suggests that the intrinsic clearances of ibuprofen, levomepromazine, and sertraline in rainbow trout can be significantly reduced as the result of P450 inhibition by pharmaceutical mixtures, whereas the clearances of diclofenac and naproxen are less impacted.

中文翻译:


虹鳟鱼肝 S9 级分中常用抗抑郁药、抗精神病药和抗炎药的体外肝清除率比较



人类药物残留在地表水中广泛存在,并可被水生生物(尤其是鱼类)吸收并在其中生物累积。评估可电离有机化合物(例如药物)的生物累积潜力的关键挑战之一是缺乏生物转化的经验数据。在本研究中,我们按照 OECD 测试指南 319B 评估了 12 种药物(单独使用或另外作为混合物使用)在虹鳟鱼肝 S9 级分 (RT-S9) 中的体外内在清除率 (CL)。测试物质包括四种抗炎药(双氯芬酸、布洛芬、酮洛芬、萘普生)、七种抗抑郁药/抗精神病药(西酞普兰、氟哌啶醇、左美丙嗪、米氮平、利培酮、舍曲林、文拉法辛)和文拉法辛的O-去甲基代谢物。检测到双氯芬酸、布洛芬、萘普生、左美丙嗪和舍曲林的可量化的内在清除率。除双氯芬酸外,其他四种药物的体外清除率严重依赖于细胞色素 P450 (CYP) 代谢。因此,我们还测定了相同 12 种药物对 CYP1A 样(7-乙氧基试卤灵-O-脱乙基化,EROD)和 CYP3A 样(苄氧基-4-三氟甲基香豆素-O-脱苄氧基化,BFCOD)的半数最大抑制浓度(IC) ) 使用 IC 位移测定的 RT-S9 活性。结果,左美丙嗪和舍曲林被认为是 EROD 和 BFCOD 活性最有效的抑制剂(未结合的 IC < 10 µM),其次是西酞普兰和氟哌啶醇(10 µM < IC < 100 µM)。此外,米氮平是一种选择性 EROD 抑制剂(IC 约 30 µM)。氟哌啶醇和舍曲林的抑制作用具有明显的时间依赖性。 最后,我们用双氯芬酸、布洛芬、萘普生、左美丙嗪和舍曲林的混合物进行了内在清除测定,以检查 EROD 和 BFCOD 抑制对其在 RT-S9 中体外 CL 的影响。我们的体外数据表明,由于药物混合物抑制 P450,虹鳟鱼中布洛芬、左美丙嗪和舍曲林的内在清除率会显着降低,而双氯芬酸和萘普生的清除率受影响较小。
更新日期:2024-08-11
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