The microsomal N-oxidation of phentermine

Area of Science:

• Biochemistry
• Pharmacology
• Drug Metabolism

Background:

• Phentermine undergoes N-oxidation, forming N-hydroxyphentermine and a nitroso compound.
• Understanding these metabolic pathways is crucial for drug safety and efficacy.

Purpose of the Study:

• To investigate the microsomal N-oxidation of phentermine (Ia) in rabbit liver.
• To elucidate the formation pathways of N-hydroxyphentermine (Ib) and alpha,alpha-dimethyl-alpha-nitroso-beta-phenylethane (Ic).

Main Methods:

• Incubation of phentermine with rabbit liver microsomal fractions (9000 g supernatant and washed microsomes).
• Utilized an NADPH generating system for optimal activity.
• Employed carbon-oxidation inhibitors to assess the role of cytochrome P-450.

Main Results:

• Maximum N-oxidation activity observed in 9000 g supernatant and microsomes with NADPH.
• Phenobarbitone pretreatment altered the ratio of Ib to Ic formation.
• Washed microsomes favored Ic formation, while 9000 g supernatant favored Ib formation.
• Cytochrome P-450 was not involved in the N-oxidation of phentermine.
• Metabolic reduction of Ic to Ib and Ib to Ia occurred in supernatant fractions.

Conclusions:

• The N-oxidation of phentermine yields N-hydroxyphentermine and a nitroso compound via independent pathways from a common N-oxidized precursor.
• Microsomal fractions and conditions significantly influence the ratio of these metabolites.
• Cytochrome P-450 is not the enzyme responsible for phentermine N-oxidation.