In vitro studies of hypoxia inducible factor-prolyl hydroxylase inhibitors daprodustat, desidustat, and vadadustat for equine doping control.
Abstract: 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.
© 2021 John Wiley & Sons, Ltd.
Publication Date: 2021-11-25 PubMed ID: 34714596DOI: 10.1002/dta.3188Google Scholar: Lookup
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- Journal Article
Summary
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The study examines the metabolic conversion processes of three hypoxia inducible factor-prolyl hydroxylase (HIF-PH) inhibitors – daprodustat, desidustat, and vadadustat – when introduced to the presence of equine liver microsomes, with implications on their potential misuse in sports for enhancing performance.
Research Strategy
- The scientists used a QExactive high-resolution mass spectrometer to examine the metabolic conversion of the HIF-PH inhibitors daprodustat, desidustat, and vadadustat in the context of equine liver microsomes.
- The aim of the study was to demonstrate how these substances, which can theoretically enhance an organism’s capacity for transporting molecular oxygen, might be transformed inside the body. This is crucial from a doping control perspective, as these substances could potentially be used to enhance sports performance.
Main Findings
- A total of 10 metabolites were detected for each of daprodustat and desidustat, whereas 15 metabolites were found in the case of vadadustat. Such metabolites are created when these substances are metabolized in the body, with variations occurring depending on the specific substance involved.
- All three substances were prone to oxidation, leading to the creation of corresponding hydroxylated metabolites. This transformation is an indication of how these substances chemically interact within the body’s metabolic systems.
- In the case of desidustat, there were observations of hydrolysis and dissociation of oxime linkage. These processes being evidence of additional metabolic reactions that the substance can undergo.
- For both desidustat and vadadustat, the glucuronic acid conjugate of the original substances was observed, along with that of the monohydroxylated analogs. However, this was not seen in the case of daprodustat. Glucuronic acid conjugation is a metabolic pathway known as glucuronidation.
- Sulfonic acid conjugated metabolites were observed only with vadadustat, showing specific metabolic characteristics related to this substance.
Implications
- The study provides critical insights into the metabolic conversions of three HIF-PH inhibitors that might potentially be misused as performance-enhancing agents in sports.
- By understanding the metabolic pathways these substances take, anti-doping authorities could be better equipped to detect and quantify these substances in the context of doping control.
Cite This Article
APA
Philip M, Karakka Kal AK, Subhahar MB, Karatt TK, Mathew B, Perwad Z.
(2021).
In vitro studies of hypoxia inducible factor-prolyl hydroxylase inhibitors daprodustat, desidustat, and vadadustat for equine doping control.
Drug Test Anal, 14(2), 317-348.
https://doi.org/10.1002/dta.3188 Publication
Researcher Affiliations
- Equine Forensic Unit, Central Veterinary Research Laboratory, Dubai, United Arab Emirates.
- Equine Forensic Unit, Central Veterinary Research Laboratory, Dubai, United Arab Emirates.
- Equine Forensic Unit, Central Veterinary Research Laboratory, Dubai, United Arab Emirates.
- Equine Forensic Unit, Central Veterinary Research Laboratory, Dubai, United Arab Emirates.
- Equine Forensic Unit, Central Veterinary Research Laboratory, Dubai, United Arab Emirates.
- Equine Forensic Unit, Central Veterinary Research Laboratory, Dubai, United Arab Emirates.
MeSH Terms
- Animals
- Barbiturates
- Doping in Sports
- Glycine / analogs & derivatives
- Horses
- Hypoxia
- Picolinic Acids
- Prolyl-Hydroxylase Inhibitors / pharmacology
- Quinolones
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This article includes 19 references
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Citations
This article has been cited 1 times.- Ishii H, Shibuya M, Kusano K, Sone Y, Kamiya T, Wakuno A, Ito H, Miyata K, Sato F, Kuroda T, Yamada M, Leung GN. 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 2022;23(10):850-865.
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