Equine Forensic Unit, Central Veterinary Research Laboratory, Dubai, United Arab Emirates.
Drug Test Anal. 2022 Feb;14(2):317-348. doi: 10.1002/dta.3188. Epub 2021 Nov 25.
Performance-enhancing substances and methods have become a serious problem in competitive sports. The hypoxia-inducible factor (HIF) stabilizers can enhance the organism's capacity for molecular oxygen transport and are likely to be abused as performance-enhancing agents in sports. This paper describes the metabolic conversion of the popular hypoxia inducible factor-prolyl hydroxylase (HIF-PH) inhibitors, namely, daprodustat, desidustat, and vadadustat using equine liver microsomes, determined on a QExactive high-resolution mass spectrometer. During this study, a total of 10 metabolites for daprodustat (all are Phase I), 10 metabolites for desidustat (five each for Phase I and Phase II), and 15 metabolites for vadadustat (six for Phase I and nine for Phase II) were detected. The important findings of the current research are as follows: (1) All the three HIF-PH inhibitor drug candidates are prone to oxidation, which results in corresponding hydroxylated metabolites; (2) in desidustat, hydrolysis and dissociation of oxime linkage also observed; (3) the glucuronic acid conjugate (except daprodustat) of the parent drugs as well as the monohydroxylated analogs were observed; (4) sulfonic acid conjugated metabolites were observed only for vadadustat.
在竞技体育中，兴奋剂和方法已成为一个严重的问题。缺氧诱导因子 (HIF) 稳定剂可以增强机体对分子氧的运输能力，很可能被滥用为运动中的兴奋剂。本文描述了在马肝微粒体中使用流行的缺氧诱导因子脯氨酰羟化酶 (HIF-PH) 抑制剂，即 daprodustat、desidustat 和 vadadustat 的代谢转化，使用 QExactive 高分辨率质谱仪进行测定。在这项研究中，共检测到 daprodustat 的 10 种代谢物（均为 I 相代谢物）、desidustat 的 10 种代谢物（各有 5 种为 I 相和 II 相代谢物）和 vadadustat 的 15 种代谢物（6 种为 I 相代谢物，9 种为 II 相代谢物）。目前研究的重要发现如下：（1）三种 HIF-PH 抑制剂候选药物都容易发生氧化，导致相应的羟基化代谢物；（2）在 desidustat 中，还观察到肟键的水解和裂解；（3）观察到母体药物的葡萄糖醛酸缀合物（除 daprodustat 外）以及单羟基化类似物；（4）仅观察到 vadadustat 的磺酸缀合代谢物。
