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Home / Equine Research Bank / Curr Drug Metab / Pharmacokinetic Study of Vadadustat and High-Resolution Mass...
Current drug metabolism2022; 23(10); 850-865; doi: 10.2174/1389200223666220825093945

Pharmacokinetic Study of Vadadustat and High-Resolution Mass Spectrometric Characterization of its Novel Metabolites in Equines for the Purpose of Doping Control.

Abstract: 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. Objective: Metabolism and elimination profiles of vadadustat in equine plasma and urine were studied for the purpose of doping control. Methods: 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. Results: 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. Conclusions: 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.
Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.
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Publication Date: 2022-08-27 PubMed ID: 36017833DOI: 10.2174/1389200223666220825093945Google Scholar: Lookup
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Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

This research article investigates the metabolism and elimination profiles of the banned substance Vadadustat in horses, with the goal of enhancing doping control measures in horse racing and equestrian competition. The researchers employed liquid chromatography high-resolution mass spectrometry to detect potential metabolites following administration of Vadadustat to three thoroughbred mares. The findings showed that Vadadustat is mainly excreted in urine as the parent drug, alongside minor metabolites. These results may contribute to more effective detection methods to prevent misuse of Vadadustat in horses.

Methods

  • The study was conducted on three thoroughbred mares, administering Vadadustat through a nasoesophageal method. The dosage was at 3 grams daily for three days.
  • The potential metabolites of Vadadustat were detected using liquid chromatography high-resolution mass spectrometry. This method allowed for a comprehensive analysis of the full-scan mass spectral data obtained in vitro with liver homogenates and post-administration samples.
  • The researchers developed and validated quantification methods that helped in establishing the excretion profiles of Vadadustat (both free and conjugates) in the plasma and urine of the mares.

Findings

  • The researchers identified a total of 23 in vivo and 14 in vitro metabolites, with 12 of these metabolites common to both categories.
  • Their analysis found that Vadadustat is primarily excreted into urine as the parent drug, with some minor conjugated metabolites also present.
  • The elimination profiles of total Vadadustat in the horses’ plasma and urine were successfully established using the developed quantification methods.

Conclusions & Implications

  • The researchers suggest that total Vadadustat could be detected for up to two weeks after administration in the plasma and urine of horses.
  • The study’s findings could aid in the development of more efficient doping control measures in horse racing and equestrian competitions. This is due to the improved understanding of the metabolic and elimination profiles of the banned substance Vadadustat.

Cite This Article

APA
Ishii H, Shibuya M, Kusano K, Sone Y, Kamiya T, Wakuno A, Ito H, Miyata K, Sato F, Kuroda T, Yamada M, Leung GN. (2022). Pharmacokinetic Study of Vadadustat and High-Resolution Mass Spectrometric Characterization of its Novel Metabolites in Equines for the Purpose of Doping Control. Curr Drug Metab, 23(10), 850-865. https://doi.org/10.2174/1389200223666220825093945

Publication

Current drug metabolism
ISSN: 1875-5453
NlmUniqueID: 100960533
Country: Netherlands
Language: English
Volume: 23
Issue: 10
Pages: 850-865

Researcher Affiliations

Ishii, Hideaki
  • 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.
Shibuya, Mariko
  • Drug Analysis Department, Laboratory of Racing Chemistry, 1731-2 Tsuruta-machi, Utsunomiya, Tochigi, Zip 320-0851, Japan.
Kusano, Kanichi
  • Veterinarian Section, Equine Department, Japan Racing Association, 6-11-1 Roppongi, Minato-ku, Tokyo, Zip 105-0003, Japan.
Sone, Yu
  • Veterinarian Section, Equine Department, Japan Racing Association, 6-11-1 Roppongi, Minato-ku, Tokyo, Zip 105-0003, Japan.
Kamiya, Takahiro
  • Equine Veterinary Clinic, Horse Racing School, Japan Racing Association, 835-1 Ne, Shiroi, Chiba, Zip 270-1431, Japan.
Wakuno, Ai
  • Equine Veterinary Clinic, Horse Racing School, Japan Racing Association, 835-1 Ne, Shiroi, Chiba, Zip 270-1431, Japan.
Ito, Hideki
  • Equine Veterinary Clinic, Horse Racing School, Japan Racing Association, 835-1 Ne, Shiroi, Chiba, Zip 270-1431, Japan.
Miyata, Kenji
  • JRA Equestrian Park Utsunomiya Office, 321-4 Tokamicho, Utsunomiya, Tochigi, Zip 320-0856, Japan.
Sato, Fumio
  • Clinical Veterinary Medicine Division, Equine Research Institute, Japan Racing Association, 1400-4, Shiba, Shimotsuke, Tochigi, Zip 329-0412, Japan.
Kuroda, Taisuke
  • Clinical Veterinary Medicine Division, Equine Research Institute, Japan Racing Association, 1400-4, Shiba, Shimotsuke, Tochigi, Zip 329-0412, Japan.
Yamada, Masayuki
  • Drug Analysis Department, Laboratory of Racing Chemistry, 1731-2 Tsuruta-machi, Utsunomiya, Tochigi, Zip 320-0851, Japan.
Leung, Gary Ngai-Wa
  • Drug Analysis Department, Laboratory of Racing Chemistry, 1731-2 Tsuruta-machi, Utsunomiya, Tochigi, Zip 320-0851, Japan.

MeSH Terms

  • Horses
  • Animals
  • Female
  • Mass Spectrometry
  • Chromatography, Liquid / methods
  • Glycine / metabolism
  • Liver / metabolism

Grant Funding

  • 2022 / JRA, Japan Racing Association

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Citations

This article has been cited 2 times.
  1. Oliveira JA, Loria F, Schobinger C, Kuuranne T, Mumenthaler C, Leuenberger N. Comparison between standard hematological parameters and blood doping biomarkers in dried blood spots within the athlete population of Swiss Sport Integrity. Front Sports Act Living 2024;6:1452079.
    doi: 10.3389/fspor.2024.1452079pubmed: 39364095google scholar: lookup
  2. Ishii H, Shigematsu R, Takemoto S, Ishikawa Y, Mizobe F, Nomura M, Arima D, Kunii H, Yuasa R, Yamanaka T, Tanabe S, Nagata SI, Yamada M, Leung GN. Quantification of osilodrostat in horse urine using LC/ESI-HRMS to establish an elimination profile for doping control. Bioanalysis 2024;16(17-18):947-958.
    doi: 10.1080/17576180.2024.2385848pubmed: 39235065google scholar: lookup
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