Metabolism of 4-methylaminorex ("EU4EA") in the rat

Metabolism studies were conducted on 4-methylaminorex (4,5-dihydro-4-methyl-5-phenyl-2-oxazolamine [4-MAX]), a potent central nervous system stimulant that has emerged as a drug of abuse under the name "EU4EA", "EU4Euh", and "Ice". Tritiated norephedrine was cyclized with cyanogen bromide to form 3H-4-MAX, which was administered to rats at a dose of 10 mg/kg orally and intravenously. Radioactivity was excreted almost entirely in urine (40% of the dose was excreted by 24 h), primarily as the parent drug (60% of the total excretions were as the parent compound). Three metabolites were identified by high-performance liquid chromatography-tandem mass spectrometry with thermospray ionization: norephedrine, 5-phenyl-4-methyl-2-oxazolidinone, and 2-amino-5-(p-hydroxyphenyl)-4-methyl-2-oxazoline. Stability studies showed that 4-MAX in aqueous solution degraded very slightly to norephedrine upon standing. There was no evidence for glucuronide or sulfate conjugation. These results suggest that the metabolic fate of 4-MAX is similar to that of the amphetamines in that it is eliminated primarily unchanged but undergoes some slight oxidative deamination and aromatic hydroxylation. Hydrolytic degradation back to the synthetic precursor can also occur. There was no evidence for the hydrolysis of the oxazolamine ring to form a urea that has been reported for the demethylated congener aminorex. This suggests that 4-methyl substitution of the oxazoline ring may inhibit metabolism similar to the alpha-methyl substitution of beta-phenylethylamines.