Investigation Into the Equine Metabolism of Phosphodiesterase-4 Inhibitor Roflumilast for Potential Doping Control.

IF 2.6 3区医学 Q2 BIOCHEMICAL RESEARCH METHODS Drug Testing and Analysis Pub Date : 2024-11-17 DOI:10.1002/dta.3822

Moses Philip, Abdul Khader Karakka Kal, Michael Benedict Subhahar, Tajudheen K Karatt, Fatma Mohammed Graiban, Meleparappil Muhammed Ajeebsanu, Marina Joseph, Shantymol V Jose

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Abstract

The phosphodiesterase 4 (PDE4) inhibitors constitute a relatively modern class of medications that are known for inducing bronchodilation and exhibiting anti-inflammatory properties within the body. Due to these properties, there is concern regarding their potential misuse as performance-enhancing substances in competitive sports. This study delves into the metabolic conversion of roflumilast in thoroughbred horses following oral administration and in vitro experimentation using equine liver microsomes and Cunninghamella elegans. High-performance liquid chromatography coupled with a Q Exactive Orbitrap mass spectrometer (HPLC-HRMS) was employed for analysis. The investigation identified 10 metabolites of roflumilast, including six phase I and four phase II metabolites from in vivo studies, and 11 metabolites from in vitro studies, consisting of eight phase I and three phase II metabolites. The identified biotransformation products encompassed processes such as hydroxylation, chlorine substitution, methylation, N-oxide formation, and even the dissociation of methylenecyclopropane and difluoromethane. Furthermore, the study identified three glucuronic acid and one sulfonic acid conjugated phase II metabolites of the investigated drug candidate. The aforementioned findings contribute to the detection and comprehension of the unauthorized utilization of roflumilast in equestrian sports.

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研究马对磷酸二酯酶-4抑制剂罗氟司特的代谢，以实现潜在的兴奋剂控制。

磷酸二酯酶 4（PDE4）抑制剂是一类相对较新的药物，以诱导支气管扩张和在体内表现出抗炎特性而闻名。由于这些特性，人们担心它们在竞技体育中可能被滥用为提高成绩的物质。本研究深入探讨了罗氟司特在纯血马口服后的代谢转化情况，并使用马肝微粒体和鞘氨醇进行了体外实验。分析采用了高效液相色谱法和 Q Exactive Orbitrap 质谱仪（HPLC-HRMS）。研究发现了罗氟司特的 10 种代谢物，包括体内研究发现的 6 种 I 期代谢物和 4 种 II 期代谢物，以及体外研究发现的 11 种代谢物，包括 8 种 I 期代谢物和 3 种 II 期代谢物。已确定的生物转化产物包括羟化、氯置换、甲基化、N-氧化物形成等过程，甚至还包括亚甲基环丙烷和二氟甲烷的解离。此外，研究还发现了所研究候选药物的三种葡萄糖醛酸和一种磺酸共轭 II 期代谢物。上述研究结果有助于发现和了解马术运动中未经授权使用罗氟司特的情况。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Drug Testing and Analysis BIOCHEMICAL RESEARCH METHODS-CHEMISTRY, ANALYTICAL

CiteScore

5.90

自引率

24.10%

发文量

191

审稿时长

2.3 months

期刊介绍： As the incidence of drugs escalates in 21st century living, their detection and analysis have become increasingly important. Sport, the workplace, crime investigation, homeland security, the pharmaceutical industry and the environment are just some of the high profile arenas in which analytical testing has provided an important investigative tool for uncovering the presence of extraneous substances. In addition to the usual publishing fare of primary research articles, case reports and letters, Drug Testing and Analysis offers a unique combination of; ‘How to’ material such as ‘Tutorials’ and ‘Reviews’, Speculative pieces (‘Commentaries’ and ‘Perspectives'', providing a broader scientific and social context to the aspects of analytical testing), ‘Annual banned substance reviews’ (delivering a critical evaluation of the methods used in the characterization of established and newly outlawed compounds). Rather than focus on the application of a single technique, Drug Testing and Analysis employs a unique multidisciplinary approach to the field of controversial compound determination. Papers discussing chromatography, mass spectrometry, immunological approaches, 1D/2D gel electrophoresis, to name just a few select methods, are welcomed where their application is related to any of the six key topics listed below.