Pérez-Pereira Ariana, Ribeiro Cláudia, Teles Filomena, Gonçalves Ricardo, M F Gonçalves Virgínia, Pereira José Augusto, Carrola João Soares, Pires Carlos, Tiritan Maria Elizabeth
CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, Gandra, Paredes, Portugal.
Interdisciplinary Center of Marine and Environmental Research, University of Porto, Edifício do Terminal de Cruzeiros do Porto de Leixões, Matosinhos, Portugal.
Environ Toxicol Chem. 2022 Mar;41(3):569-579. doi: 10.1002/etc.4955. Epub 2021 Mar 10.
Ketamine is a chiral drug used for various clinical purposes but often misused. It is metabolized to norketamine, an active chiral metabolite. Both substances have been detected in environmental matrices, but studies about their enantioselective toxic effects are scarce. In the present study, the enantiomers of ketamine and norketamine were separated by a semipreparative enantioselective liquid chromatography method, and their toxicity was investigated in different aquatic organisms. The enantioseparation was achieved using a homemade semipreparative chiral column. Optimized conditions allowed the recovery of compounds with enantiomeric purity higher than 99%, except for (R)-ketamine (97%). The absolute configuration of the enantiomers was achieved by experimental electronic circular dichroism (ECD). The ecotoxicity assays were performed with the microcrustacean Daphnia magna and the protozoan Tetrahymena thermophila using Toxkit MicroBioTests. Different concentrations were tested (0.1-10 000 µg/L) to include environmental levels (0.5-100 µg/L), for racemates (R,S) and the isolated enantiomers (R or S) of ketamine and norketamine. No toxicity was observed in either organism at environmental levels. However, at greater concentrations, (R,S)-ketamine presented higher mortality for D. magna compared with its metabolite (R,S)-norketamine (85 and 20%, respectively), and the (S)-ketamine enantiomer showed higher toxicity than the (R)-ketamine enantiomer. In addition, (S)-ketamine also presented higher growth inhibition than (R)-ketamine for T. thermophila at the highest concentrations (5000 and 10 000 µg/L). Contrary to D. magna, growth inhibition was observed for both enantiomers of norketamine and in the same magnitude order of the (S)-ketamine enantiomer. The results showed that the 2 organisms had different susceptibilities to norketamine and that the toxicity of ketamine at high concentrations is enantioselective for both organisms. Environ Toxicol Chem 2022;41:569-579. © 2020 SETAC.
氯胺酮是一种用于多种临床目的但常被滥用的手性药物。它会代谢为去甲氯胺酮，一种具有活性的手性代谢物。这两种物质都已在环境基质中被检测到，但关于它们对映体选择性毒性作用的研究却很少。在本研究中，氯胺酮和去甲氯胺酮的对映体通过半制备型对映体选择性液相色谱法进行分离，并在不同水生生物中研究了它们的毒性。对映体拆分是使用自制的半制备型手性柱实现的。优化后的条件能够回收对映体纯度高于99%的化合物，但（R）-氯胺酮除外（97%）。对映体的绝对构型通过实验性电子圆二色光谱（ECD）确定。使用Toxkit MicroBioTests对微型甲壳动物大型溞和原生动物嗜热四膜虫进行了生态毒性测定。测试了不同浓度（0.1 - 10000 µg/L），以涵盖环境水平（约0.5 - 约100 µg/L），包括氯胺酮和去甲氯胺酮的外消旋体（R,S）以及分离出的对映体（R或S）。在环境水平下，两种生物均未观察到毒性。然而，在更高浓度下，（R,S）-氯胺酮对大型溞的致死率高于其代谢物（R,S）-去甲氯胺酮（分别为85%和20%），并且（S）-氯胺酮对映体的毒性高于（R）-氯胺酮对映体。此外，在最高浓度（5000和10000 µg/L）下，（S）-氯胺酮对嗜热四膜虫的生长抑制也高于（R）-氯胺酮。与大型溞相反，去甲氯胺酮的两种对映体均观察到生长抑制，且与（S）-氯胺酮对映体的抑制程度相同。结果表明，这两种生物对去甲氯胺酮的敏感性不同，并且高浓度下氯胺酮对两种生物的毒性具有对映体选择性。《环境毒理学与化学》2022年；41:569 - 579。© 2020 SETAC。
