Drug Analysis Department, Laboratory of Racing Chemistry, 1731-2 Tsuruta-machi, Utsunomiya, Tochigi, Zip 320-0851, Japan.
Department of Pharmaceutical Sciences, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, Zip 980-8574, Japan.
Curr Drug Metab. 2022;23(10):850-865. doi: 10.2174/1389200223666220825093945.
Vadadustat, a hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) inhibitor, is a substance which carries a lifetime ban in both horse racing and equestrian competition. A comprehensive metabolic study of vadadustat in horses has not been previously reported.
Metabolism and elimination profiles of vadadustat in equine plasma and urine were studied for the purpose of doping control.
A nasoesophageal administration of vadadustat (3 g/day for 3 days) was conducted on three thoroughbred mares. Potential metabolites were comprehensively detected by differential analysis of full-scan mass spectral data obtained from both in vitro studies with liver homogenates and post-administration samples using liquid chromatography high-resolution mass spectrometry. The identities of metabolites were further substantiated by product ion scans. Quantification methods were developed and validated for the establishment of the excretion profiles of the total vadadustat (free and conjugates) in plasma and urine.
A total of 23 in vivo and 14 in vitro metabolites (12 in common) were identified after comprehensive analysis. We found that vadadustat was mainly excreted into urine as the parent drug together with some minor conjugated metabolites. The elimination profiles of total vadadustat in post-administration plasma and urine were successfully established by using quantification methods equipped with alkaline hydrolysis for cleavage of conjugates such as methylated vadadustat, vadadustat glucuronide, and vadadustat glucoside.
Based on our study, for effective control of the misuse or abuse of vadadustat in horses, total vadadustat could successfully be detected for up to two weeks after administration in plasma and urine.
vadadustat 是一种低氧诱导因子脯氨酰羟化酶（HIF-PHD）抑制剂，在赛马和马术比赛中被终身禁止使用。vadadustat 在马体内的代谢研究尚未见报道。
研究 vadadustat 在马血浆和尿液中的代谢和消除特征，以便进行兴奋剂控制。
对 3 匹纯种母马进行鼻胃管给药vadadustat（3 克/天，连续 3 天）。通过对体外肝匀浆和给药后样品的全扫描质谱数据进行差异分析，综合检测潜在的代谢物。通过产物离子扫描进一步证实代谢物的身份。建立了定量方法，用于确定血浆和尿液中总vadadustat（游离和缀合物）的排泄特征。
经综合分析，共鉴定出 23 种体内代谢物和 14 种体外代谢物（其中 12 种代谢物相同）。我们发现，vadadustat 主要以原形药物和一些少量的缀合代谢物从尿液中排泄。通过使用配备碱性水解的定量方法，可以成功建立给药后血浆和尿液中总vadadustat 的消除特征，用于裂解缀合代谢物，如甲基化 vadadustat、vadadustat 葡萄糖醛酸苷和 vadadustat 葡萄糖苷。
根据我们的研究，为了有效控制马体内 vadadustat 的误用或滥用，在血浆和尿液中，给药后两周内可成功检测到总vadadustat。
