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Abstract

Dextrorphan is a Phase I equine metabolite of dextromethorphan, a widely used anti-tussive / cough suppressant medication marketed and available in numerous over-the-counter formulations in the United States. Dextromethorphan is an Association of Racing Commissioners International (ARCI) drug class 4 penalty class B substance and a Horseracing Integrity and Welfare Authority (HIWU) CONTROLLED S7 B substance and is regulated as such in horse racing. In horses, dextromethorphan is metabolized to its Phase I metabolite, dextrorphan, which is next glucuronidated and the resultant dextrorphan-glucuronide conjugate then excreted at remarkably high concentrations in equine urine. Dextrorphan is therefore at times identified in equine urine samples at low nanogram/ml concentrations and the question arises as to the origins and the pharmacological and/or regulatory significance of such low concentration urinary identifications. In the 2015-2016 winter season three low concentration urinary identifications of dextrorphan were reported in Kentucky Thoroughbred racing, to our knowledge all less than 20 ng/ml concentrations with the last identification occurring in a race on April 21st, 2016. Soon thereafter published scientific research on dextromethorphan in horses became available and based on review of this published data the Kentucky Horse Racing Commission (KHRC) elected to rescind these three urinary dextrorphan identifications. Given the less than 20 nanograms/ml communicated concentrations of dextrorphan in these rescinded identifications and the published research on dextromethorphan in horses, these regulatory actions are consistent with urinary dextrorphan concentrations of less than 20 nanograms/ml as being pharmacologically irrelevant and therefore not, per se, of regulatory significance. Further analysis of the published research on post-administration plasma concentrations of dextromethorphan show mean peak plasma concentrations of dextromethorphan of 442 ng/ml, with no evidence of quantifiable pharmacological responses. Conservative interpretation of this 442 nanograms/ml plasma concentration of dextromethorphan as an Effective Plasma Concentration (EPC) and dividing this EPC by the conservative Toutain safety factor of 500 yields an Irrelevant Plasma Concentration (IPC) of 884 picograms/ml, which concentration rounded up to 1 nanogram/ml we now present as an interim regulatory Screening Limit / ”cut-off” for dextromethorphan in equine plasma or serum samples, with urinary detections of recovered post enzymatic-hydrolysis dextrorphan concentrations alone not considered appropriate for regulatory action.

Document Type

Article

Publication Date

2026

Digital Object Identifier (DOI)

DOI 10.21836Compendium20260103

Funding Information

This research was made possible by research support from The Equine Health and Welfare Alliance, Inc, Versailles, Kentucky, and the United States Trotting Association, Columbus, OH. Further support came from the National Institute of Food and Agriculture, U.S. Department of Agriculture, Hatch Program under project KY014066 Accession Number 7001029. Other support includes research support from The National Horsemen’s Benevolent and Protective Association and the Alabama, Arizona, Arkansas, Ontario, Canada; Charles Town, WV; Florida, Indiana, Iowa, Kentucky, Louisiana, Michigan, Minnesota, Nebraska, Ohio, Oklahoma, Oregon, Pennsylvania, Tampa Bay Downs, Florida, Texas, Washington State, and West Virginia Horsemen’s Benevolent and Protective Associations.

Funding sources provided no role in the design of the study, nor in the collection, analysis, and interpretation of all presented and referenced data.

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