Philip Moses, Karakka Kal Abdul Khader, Mathew Binoy, Subhahar Michael Benedict, Karatt Tajudheen K, Perwad Zubair
Equine Forensic Unit, Central Veterinary Research Laboratory, Dubai, United Arab Emirates.
Drug Test Anal. 2022 Oct;14(10):1703-1723. doi: 10.1002/dta.3348. Epub 2022 Jul 26.
A number of erythropoiesis stimulants are entering the final stage of clinical trials due to recent scientific progress in hypoxia-regulated erythropoiesis. Considering how erythropoiesis-stimulating compounds enhance the capacity of the organism to transport oxygen, they pose a great risk of being misused as performance enhancers. In this paper, we report the metabolic fate of three popular hypoxia-inducible factor-prolyl hydroxylase Inhibitors (HIF-PHI) compounds, namely, BAY 87-2243, MK-8617, and PT-2385 in equine liver microsomes using Q-Exactive high-resolution mass spectrometry. This study found 22 metabolites for BAY 87-2243 (19 phase I and three phase II), three metabolites for MK-8617 (all phase I), and five metabolites for PT-2385 (two phase I and three phase II). The major findings of the present study are as follows: (1) all three potential HIF-PHI drug candidates, namely, BAY 87-2243, MK-8617, and PT-2385 are susceptible to oxidation, producing their corresponding hydroxylated metabolites; (2) the ring dissociated metabolites were detected for BAY 87-2243 and PT-2385; (3) in the case of BAY 87-2243 and PT-2385, glucuronic acid conjugated metabolites were detected; and (4) none of the drugs produced sulfonic acid conjugated metabolites.
由于缺氧调节红细胞生成方面的最新科学进展，一些红细胞生成刺激剂正进入临床试验的最后阶段。考虑到红细胞生成刺激化合物如何增强机体运输氧气的能力，它们存在被滥用为性能增强剂的巨大风险。在本文中，我们使用Q-Exactive高分辨率质谱法报告了三种常见的缺氧诱导因子脯氨酰羟化酶抑制剂（HIF-PHI）化合物，即BAY 87-2243、MK-8617和PT-2385在马肝微粒体中的代谢命运。本研究发现BAY 87-2243有22种代谢物（19种I相和3种II相），MK-8617有3种代谢物（均为I相），PT-2385有5种代谢物（2种I相和3种II相）。本研究的主要发现如下：（1）所有三种潜在的HIF-PHI候选药物，即BAY 87-2243、MK-8617和PT-2385都易被氧化，产生相应的羟基化代谢物；（2）检测到BAY 87-2243和PT-2385的环解离代谢物；（3）在BAY 87-2243和PT-2385的情况下，检测到葡萄糖醛酸共轭代谢物；（4）没有一种药物产生磺酸共轭代谢物。
