Mapping the Metabolic Fate of Suzetrigine in Equine and Camel Models: A Step Toward Reliable Antidoping Detection

Abstract

Rationale

Effective pain management remains a persistent challenge, with opioids limited by tolerance, dependence, respiratory depression, and misuse. This has created demand for safer, nonaddictive alternatives. Suzetrigine (VX-548, Journavx) is a novel analgesic with promising efficacy, but its potential misuse in competitive racing requires investigation. Limited information is available on its metabolism and detection, emphasizing the need for metabolic characterization to aid antidoping strategies.

Methods

In vitro metabolism of suzetrigine was evaluated using equine liver microsomes and homogenized camel liver. Metabolic profiling was carried out using high-resolution LC–HRMS. Fragmentation analysis was performed to assign metabolite structures and characterize biotransformation pathways.

Results

Seven phase I metabolites (M1–M7) were identified, primarily via hydroxylation, methylation, demethylation, detrifluoromethylation, and cleavage of the pyridine-2-carboxamide moiety. One phase II metabolite (M8), formed by sulfation of the demethylated metabolite M5, was detected exclusively with camel liver. Metabolite structures were tentatively assigned based on mass fragmentation data, which showed characteristic neutral losses and diagnostic ions. Comparative analysis revealed that both species shared common phase I pathways, but camel liver demonstrated additional conjugation capacity.

Conclusion

This study provides the first comprehensive characterization of suzetrigine metabolism in equine and camel liver systems. The results underscore metabolic variations, propose a biotransformation pathway, and offer crucial insights to support the development of antidoping detection strategies.