Pemoline, a central nervous system stimulant reportedly occurring naturally in equine samples in Europe and elsewhere – a review and analysis

Abstract

Pemoline, (RS)-2-amino-5-phenyl-1,3-oxazol-4(5H)-one, is a member of the 4-oxazolidinone group of substances and a central nervous system stimulant closely related structurally and pharmacologically to aminorex. With the increased sensitivity of equine drug testing, low concentration identifications of pemoline have increasingly been identified in horse racing. In 2009 two pemoline and one tetramisole identification in English racing were reported in horses administered levamisole, leading to suggestions that levamisole, known to metabolize to aminorex, could also metabolize to pemoline. In April 2016 the French, German, and South African horseracing laboratories reported frequent identifications of pemoline in equine urine samples, such that these laboratories had “in-house” reporting limits below which urinary pemoline identifications were not reported. In 2016 and again in 2018 the matter of potential pemoline identifications in Indiana horse rac ing was communicated by the Indiana Horse Racing Commission to Indiana horsemen, with requests that horsemen avoid use of levamisole. Soon thereafter, in late 2018, we became aware that plant barbarin was a potential source of equine urinary aminorex identifications. In Spring 2019 we therefore harvested flowering “Yellow Rocket” (Barbarea vulgaris), a barbarin-containing invasive plant widely distributed in North America and administered it orally to horses. Urine samples collected from these horses were found to contain aminorex. Aminorex, closely related chemically and pharmacologically to pemoline, is therefore a naturally occurring alkaloid that may be identified in equine urine, suggesting possible similar botanical origins for pemoline, now not infrequently being identified at low ng/mL concentrations in equine urine samples in Europe and elsewhere. Addressing the regulatory implications of these findings, we have therefore reviewed the pharmacological literature on pemoline in the horse and using the Toutain & Lassourd safety factor of 500 we now propose 2 ng/mL of pemoline as an Irrelevant Plasma Concentration (IPC) of pemoline in horses.