The Influence of Metabolism on the MAO-B Inhibitory Potency of Selegiline

Abstract

(-)-Deprenyl (selegiline), a propargylamine derivative of methylamphetamine, is a potent, irreversible inhibitor of monoamine-oxidase type B (MAO-B). The MAO-B inhibitory effects of various doses (0.1-0.25-0.5 mg/kg) of (-)-deprenyl in rat brain and liver were compared, using either oral or subcutaneous drug administration. The intensity of the first pass metabolism of (-)-deprenyl was also estimated. The effect of pre-treatment with phenobarbitone (80 mg/kg i.p., daily for three days) or proadifen (SKF-525A, 50 mg/kg i.p., single dose) on the MAO-B inhibitory potency of (-)-deprenyl was also studied. The oral and subcutaneous administration of selegiline induced a significantly different degree of MAO-B enzyme inhibition in the rat brain, but not in the liver. The inhibitory potency of (-)-deprenyl on MAO-B activity was markedly influenced by pre-treatment of rats with an inducer (phenobarbitone), or an inhibitor (SKF-525A) of cytochrome P-450 mono-oxygenases in the liver. Our results suggest, that (-)-deprenyl is metabolised mainly in the liver by microsomal cytochrome P-450 dependent mono-oxygenases, and it has an intensive first-pass metabolism. The parent compound is responsible for the inhibition of MAO-B enzyme activity.

R-Deprenyl: Pharmacological Spectrum of its Activity

“…Concomitant food consumption has increased the absorbed amount of R-deprenyl by about three times, without changing the plasma concentration of its metabolites [5]. Since the parent compound is responsible for the inhibition of MAO-B enzyme, there is a considerable difference in the brain enzyme activity following oral or parenteral drug administration [25]. Recently, orally disintegrating dosage form of R-deprenyl has been developed, avoiding first pass metabolism.…”

Selegiline reduces adiposity induced by high‐fat, high‐sucrose diet in male rats

“…Despite all our efforts, our study has certain limitations. Although we did not measure the activity of MAO‐B in different organs in this project, we have applied a dose of selegiline widely used in rats that was reported to effectively inhibit MAO‐B in several organs (Knoll, ; Heinonen et al ., ; Haberle et al ., ). Neither diet nor selegiline had any influence on adipocyte area and weight of interscapular brown adipose tissue.…”

Metabolic Transformation Plays a Primary Role in the Psychostimulant-Like Discriminative-Stimulus Effects of Selegiline [(R)-(–)-Deprenyl]

“…Administration of a 50 mg/kg dose of SKF 525A, which is fully effective in blocking the CYP450 enzyme responsible for the metabolism of (R)-(Ϫ)-deprenyl (Engberg et al, 1991;Haberle et al, 2002;, completely blocked, or significantly reduced, the ability of (R)-(Ϫ)-deprenyl to produce generalization to (S)-(ϩ)-methamphetamineand cocaine-training stimuli under both the food presentation and stimulus shock termination schedules. In previous experiments with rats (Engberg et al, 1991), (R)-(Ϫ)-methamphetamine, in doses relevant to the formation of (R)-(Ϫ)-methamphetamine metabolites from (R)-(Ϫ)-deprenyl (Melega et al, 1999), produced locomotor activation effects similar to those of (R)-(Ϫ)-deprenyl and the effects of (R)-(Ϫ)-deprenyl, but not those of (R)-(Ϫ)-methamphetamine, were blocked by pretreatment with 50 mg/kg SKF 525A.…”