The metabolism of l-N-benzyl-β-methoxy-3-trifluoromethylphenethylamine hydrochloride in the rat, dog, monkey and man

Abstract l -N-benzyl-β-methoxy-3-trifluoromethylphenethylamine hydrochloride, an anorectic agent, was administered to rats, dogs, monkeys and man, employing either the 14 C labeled or nonistopic drug. The compound was essentially completely absorbed. A major portion of the dose was excreted during the first 24 hr; however, drug-related material continued to be slowly excreted over a 96-hr collection period. Urinary excretion of drug-related material, as compared to fecal excretion, was slightly lower in the rat and approximately twice as high in the dog. Urinary excretion in the monkey was in the same range as seen in the dog. Human urinary excretion of dose was comparable to that of the rat. Fecal excretion was not measured in the latter two species. Rat biliary excretion of over 50 % of dose in 24 hr showed the bile to be an important excretion route in this species. Plasma levels of drug-related material were prolonged in all species studied. These levels, when measured in monkeys, remained relatively constant during a 24-hr sampling period. The remaining three species showed plasma parent compound half-lives of approximately 3–4 hr. The desbenzyl metabolite and total drug-related material half-lives were in the range of 7–9 hr. Drug distribution in tissues was highest in concentration in the vascular organs i.e. liver, lungs, kidneys and spleen. Brain tissue in rats contained only basic drug-related material which was predominantly the desbenzyl metabolite. Only a trace of unchanged parent compound was present. Metabolites, identified by a combination of thin-layer and gas chromatography, by mass spectral and isotope dilution analyses, were trifluoromethyl-O-methylphenethylamine, trifluoromethyl-O-methylmandelic acid, trifluoromethylmandelic acid and trifluoromethylhippuric acid. Conjugation of the desbenzyl metabolite as a glucuronide was found in dog and monkey, indicated in man, but not found in the rat. Assay methods specific for the drug and the desbenzyl metabolite (gas chromatography) and a nonspecific method which measured the organically bound fluorine of the compound were developed and applied to plasma and urine specimens.