Voxelotor, a sickle cell drug now banned by WADA, was studied in Thoroughbred horses after oral dosing. LC-HRMS identified 35 metabolites, mainly via hydroxylation, reduction, glucuronidation, and sulfation. Major metabolites showed extended detection times, aiding antidoping efforts. Blood analyses also indicated notable hematological changes requiring further investigation.

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.