Metabolism of phentermine and its derivatives in the male Wistar rat.

1. Urinary metabolites of the male Wistar rat dosed i.p. and orally with phentermine (Ph), N-hydroxyphentermine (N-hydroxy-Ph) and p-hydroxyphentermine (p-hydroxy-Ph) were examined by g.l.c. and g.l.c.-mass spectroscopy. 2. N-hydroxy-Ph which accounted for about 3% dose was identified in the urine of rat dosed i.p. and orally with Ph. The major urinary metabolite of Ph dosed i.p. and orally was a p-hydroxy-Ph conjugate (51% dose). 3. The major urinary metabolite of N-hydroxy-Ph dosed i.p. and orally was a p-hydroxy-Ph conjugate (40% dose). A N-hydroxy-Ph conjugate (12% dose) was identified following i.p. administration of N-hydroxy-Ph, but was not detected following oral administration. Small amounts of Ph (< 10% dose) and p-hydroxy-Ph (3% dose) were also identified after i.p. and oral administration of N-hydroxy-Ph. 4. The only urinary metabolite of p-hydroxy-Ph after either i.p. or oral dosing was a p-hydroxy-Ph conjugate (65% dose). 5. These results indicate that N-hydroxy-Ph is a urinary metabolite of Ph in rat; p-hydroxy-Ph is produced by the hydroxylation of Ph itself and partly by the hydroxylation of Ph formed from N-hydroxy-Ph; the p-hydroxy-Ph conjugate is the major and final metabolite of Ph dosed i.p. and orally.