The metabolism of 1-phenyl-2-(N-methyl-N-furfurylamino)propane (furfenorex) in the rat in vivo and in vitro.

The metabolism of 1-phenyl-2-(N-methyl-N-furfurylamino)propane (furfenorex) was studied in the rat in vivo and in vitro. Nine metabolites with only traces of the unchanged drug were obtained from urine after oral administration of furfenorex to rats. The major metabolite was an acidic compound, isolated and identified as 1-phenyl-2-(N-methyl-N-gamma-valerolactonylamino)propane. Amphetamine, methamphetamine and their hydroxylated metabolites were excreted as minor metabolites. Metabolites excreted in two days after administration of the drug amounted to about 20% of dose. The acidic metabolite, a major metabolite in vivo, was not detected after incubation of furfenorex with rat-liver microsomes. The major metabolic routes of furfenorex in vitro were N-demethylation and N-defurfurylation which produced 1-phenyl-2-(N-furfurylamino)propane (furfurylamphetamine) and methamphetamine, respectively. The formation of furfurylamphetamine and methamphetamine were catalysed by rat-liver microsomes supplemented with NADPH and O2, and were inhibited by either SKF 525-A or CO. The formation of both metabolites were inhibited by 2-methyl-1,2-bis-(3-pyridyl)-1-propanone (metyrapone), but not by 7,8-benzoflavone. They were enhanced by pretreatment of rats with phenobarbitone, but not with 3-methylcholanthrene. These data suggested that N-demethylation and N-defurfurylation of furfenorex were mainly mediated by cytochrome P-450 but not cytochrome P-448.