The Disposition of Phentermine and its N-Oxidized Metabolic Products in the Rabbit

Abstract

1. When phentermine was injected intraperitoneally to rabbits, 77% of the dose was excreted in the urine within 2 days; N-oxidized metabolic products accounted for 62% dose. Major excretion products were N-hydroxyphentermine (28% dose), conjugated N-hydroxyphentermine (32% dose) and unchanged phentermine (16% dose).

2. Similarly injected N-hydroxyphentermine was excreted (62% dose) in the urine in 2 days; only 4% dose was recovered unchanged. Major routes of metabolism of N-hydroxyphentermine were conjugation (36% dose) and reduction to the parent amine (15% dose). Conditions for hydrolysis of urine to liberate N-hydroxyphentermine from its conjugates were studied; N-hydroxyphentermine decomposes in strong acid.

3. Only 10% of injected α,α-dimethyl-α-nitroso-β-phenylethane was excreted in the urine in 2 days.

4. N-Oxidation is the major pathway of metabolism of phentermine in rabbits; the present results suggest that some biological activity may be mediated by the pharmacologically active N-hydroxyphentermine.