Equine Metabolism of Voxelotor and Its Impact on Hematological Indices: A Doping Control Perspective.
Abstract: Voxelotor, a therapeutic drug for sickle cell disease, has been reported to elevate serum erythropoietin and hemoglobin levels in healthy individuals. Because of its potential to alter blood parameters, the World Anti-Doping Agency (WADA) classified voxelotor under category M1 of the 2023 Prohibited List. Despite this classification, little is known about its metabolic behavior in either humans or animals. In this study, the metabolism of voxelotor was investigated in Thoroughbred horses after oral administration. Using liquid chromatography high-resolution mass spectrometry (LC-HRMS), 35 metabolites were detected. Among them, the most prominent pathways included hydroxylation and reductive transformations (Phase I), as well as glucuronidation and sulfonation (Phase II). Notably, several glucuronide conjugates and hydroxylated derivatives were identified as major metabolites, with extended detection times that make them particularly relevant for antidoping surveillance. Blood analyses also revealed changes in red blood cell count, hemoglobin concentration, packed cell volume, and platelet levels. Together, these findings provide practical insight into voxelotor's metabolic profile in equines and highlight specific metabolites useful for doping control. Further studies are needed to better define its hematological impact and to confirm whether the observed clinical effects are drug related.
© 2025 John Wiley & Sons Ltd.
Publication Date: 2025-10-09 PubMed ID: 41063632DOI: 10.1002/dta.3957Google Scholar: Lookup
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- Journal Article
Summary
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Overview
- This study explores how the drug voxelotor is metabolized in horses and examines its effects on blood parameters, providing important information for doping control in equine sports.
Background
- Voxelotor is a medication approved to treat sickle cell disease by improving hemoglobin function.
- It has been found to increase erythropoietin (a hormone promoting red blood cell production) and hemoglobin levels in healthy humans.
- Because it can alter blood parameters, the World Anti-Doping Agency (WADA) added voxelotor to its 2023 Prohibited List under category M1, which covers substances that affect oxygen transport.
- Despite its clinical use and doping concerns, the metabolism of voxelotor in humans and animals is poorly understood.
Objectives of the Study
- To characterize the metabolic profile of voxelotor in Thoroughbred horses following oral administration.
- To identify relevant metabolites that could be used as biomarkers for doping control.
- To assess the impact of voxelotor on hematological indices such as red blood cell count and hemoglobin concentration in horses.
Methods
- Voxelotor was administered orally to Thoroughbred horses.
- Blood samples were collected and analyzed using liquid chromatography with high-resolution mass spectrometry (LC-HRMS) to detect and characterize metabolites.
- Hematological parameters including red blood cells, hemoglobin concentration, packed cell volume, and platelet levels were monitored.
Key Findings: Metabolic Profile
- A total of 35 different voxelotor metabolites were identified in the horse samples.
- Main metabolic pathways observed include:
- Phase I reactions: hydroxylation (addition of hydroxyl groups) and reductive transformations (chemical reductions).
- Phase II reactions: conjugation via glucuronidation and sulfonation, which typically increase metabolite solubility and excretion.
- Several glucuronide conjugates and hydroxylated derivatives were the major metabolites detected.
- These metabolites showed extended detection times, highlighting their suitability as targets for anti-doping testing protocols.
Key Findings: Hematological Changes
- Blood analyses revealed changes in important parameters after voxelotor administration:
- Red blood cell count increased.
- Hemoglobin concentration elevated.
- Packed cell volume (proportion of blood volume made up of red cells) was altered.
- Platelet levels were also affected.
- These changes may impact oxygen transport efficiency and blood viscosity.
- The findings align with voxelotor’s known effects in humans but require further investigation to determine clinical relevance in horses.
Implications for Doping Controls
- The identified metabolites, especially glucuronide conjugates and hydroxylated derivatives, offer practical targets for detecting voxelotor use in racehorses.
- Extended detection windows improve the ability of doping labs to identify illicit voxelotor administration well after dosing.
- Changes in hematological indices due to voxelotor could potentially enhance race performance, justifying WADA’s inclusion of voxelotor in the prohibited list.
- Testing strategies can now be better informed with this metabolic and hematological data to ensure fair competition and horse welfare.
Conclusions and Future Directions
- This study provides the first comprehensive profile of voxelotor metabolism in horses and highlights important hematological effects relevant to doping considerations.
- Further studies are needed to:
- Clarify the direct relationship between voxelotor administration and observed blood parameter changes.
- Understand the pharmacokinetics and pharmacodynamics of voxelotor in equines more thoroughly.
- Refine testing methods to improve sensitivity and specificity for doping control labs.
- Evaluate the potential impacts on horse health and performance over longer periods.
Cite This Article
APA
Kal AKK, Subhahar MB, Philip M, Graiban FM, Karatt TK, Mathew B, George RM, Maruthasalam B.
(2025).
Equine Metabolism of Voxelotor and Its Impact on Hematological Indices: A Doping Control Perspective.
Drug Test Anal, 17(12), 2447-2460.
https://doi.org/10.1002/dta.3957 Publication
Researcher Affiliations
- Equine Forensic Unit, Central Veterinary Research Laboratory, Dubai, UAE.
- Equine Forensic Unit, Central Veterinary Research Laboratory, Dubai, UAE.
- Equine Forensic Unit, Central Veterinary Research Laboratory, Dubai, UAE.
- Equine Forensic Unit, Central Veterinary Research Laboratory, Dubai, UAE.
- Equine Forensic Unit, Central Veterinary Research Laboratory, Dubai, UAE.
- Equine Forensic Unit, Central Veterinary Research Laboratory, Dubai, UAE.
- Haematology and Biochemistry, Central Veterinary Research Laboratory, Dubai, UAE.
- Haematology and Biochemistry, Central Veterinary Research Laboratory, Dubai, UAE.
MeSH Terms
- Horses / metabolism
- Horses / blood
- Animals
- Doping in Sports / prevention & control
- Substance Abuse Detection / methods
- Hemoglobins / analysis
- Chromatography, Liquid / methods
- Male
- Pyrazoles / metabolism
- Pyrazoles / administration & dosage
- Pyrazines / metabolism
- Erythrocyte Count
- Tandem Mass Spectrometry / methods
- Administration, Oral
References
This article includes 21 references
- Modell B, Darlison M. Global Epidemiology of Haemoglobin Disorders and Derived Service Indicators. Bulletin of the World Health Organization 86, no. 6 (2008): 480–487.
- Serjeant GR, Serjeant BE, Fraser RA. Hb S‐β‐Thalassemia: Molecular, Hematological and Clinical Comparisons. Hemoglobin 35, no. 1 (2011): 1–12.
- Chakravorty S, Williams TN. Sickle Cell Disease: A Neglected Chronic Disease of Increasing Global Health Importance. Archives of Disease in Childhood 100 (2015): 48–53.
- AlDallal SM. Voxelotor: A Ray of Hope for Sickle Disease. Cureus 12, no. 2 (2020): e7105.
- Blair HA. Voxelotor: First Approval. Drugs 80, no. 2 (2020): 209–215.
- Vissa M, Vichinsky E. Voxelotor for the Treatment of Sickle Cell Disease. Expert Review of Hematology 14, no. 3 (2021): 253–262.
- Glaros AK, Razvi R, Shah N, Zaidi AU. Voxelotor: Alteration of Sickle Cell Disease Pathophysiology by a First‐in‐Class Polymerization Inhibitor. Therapeutic Advances in Hematology 12 (2021): 20406207211001136.
- Hutchaleelaha A, Patel M, Washington C. Pharmacokinetics and Pharmacodynamics of Voxelotor (GBT440) in Healthy Adults and Patients With Sickle Cell Disease. British Journal of Clinical Pharmacology 85, no. 6 (2019): 1290–1302.
- Dufu K, Patel M, Oksenberg D, Cabrales P. GBT440 Improves Red Blood Cell Deformability and Reduces Viscosity of Sickle Cell Blood Under Deoxygenated Conditions. Clinical Hemorheology and Microcirculation 70, no. 1 (2018): 95–105.
- European Medicines Agency, “Oxbryta: EPAR‐Product Information EMEA/H/C/004869,” (2022).
- Green ML, Savic RM, Tonda M, Jorga K, Washington CB. Model‐Informed Drug Development of Voxelotor in Sickle Cell Disease: Exposure‐Response Analysis to Support Dosing and Confirm Mechanism of Action. CPT: Pharmacometrics & Systems Pharmacology 11, no. 6 (2022): 698–710.
- Oksenberg D, Dufu K, Patel MP. GBT440 Increases Haemoglobin Oxygen Affinity, Reduces Sickling and Prolongs RBC Half‐Life in a Murine Model of Sickle Cell Disease. British Journal of Haematology 175, no. 1 (2016): 141–153.
- Han J, Saraf SL, Gordeuk VR. Systematic Review of Voxelotor: A First‐in‐Class Sickle Hemoglobin Polymerization Inhibitor for Management of Sickle Cell Disease. Pharmacotherapy 40, no. 6 (2020): 525–534.
- World Anti‐Doping Agency, List of Prohibited Substances and Methods (World Anti‐Doping Code Int Stand, 2023).
- Rademacher P, Hutchaleelaha A, Washington C, Lehrer J, Ramos E. Absorption, Metabolism and Excretion of GBT440, a Novel Hemoglobin S (HbS) Polymerization Inhibitor for the Treatment of Sickle Cell Disease (SCD), in Healthy Male Subjects. Blood 128, no. 22 (2016): 2487.
- Rzeppa S, Voss SC, Thieme D, Keiler AM. Identification of Human In Vitro Metabolites of the Haemoglobin S Polymerization Inhibitor Voxelotor for Doping Control Purposes. Drug Testing and Analysis 15 (2023): 1403–1409.
- Liang X, Tian T, Zheng Z, Geng H, Shan Y, Deng X. Metabolic Profile Characterization of Voxelotor in Human Urine Based on In Vivo and In Vitro Models for Doping Control. Analytical and Bioanalytical Chemistry 416, no. 28 (2024): 6575–6588.
- Subhahar MB, Karakka Kal AK, Philip M, Muhammed Ajeebsanu M, Karatt TK, Perwad Z. Doping Control Approach: Identification of Equine In Vitro Metabolites of Voxelotor (GBT440), a Hemoglobin S Polymerization Inhibitor. Rapid Communications in Mass Spectrometry 38, no. 2 (2024): e9671.
- Philip M, K K Kal AK, Subhahar MB. Equine Metabolic Investigation of the Phosphodiesterase‐4 Inhibitor Ibudilast as a Potential Performance Enhancer. Rapid Communications in Mass Spectrometry 38, no. 23 (2024): e9916.
- Philip M, Karakka Kal AK, Subhahar MB. Investigation Into the Equine Metabolism of Phosphodiesterase‐4 Inhibitor Roflumilast for Potential Doping Control. Drug Testing and Analysis 17, no. 7 (2025): 1219–1231.
- Estepp JH. Voxelotor (GBT440), a First‐in‐Class Hemoglobin Oxygen‐Affinity Modulator, Has Promising and Reassuring Preclinical and Clinical Data. American Journal of Hematology 93, no. 3 (2018): 326–329.
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