Pharmacokinetic aspects of l-deprenyl (selegiline) and its metabolites*

Abstract

l‐Deprenyl (selegiline), an irreversible and selective inhibitor of monoamine oxidase type B (MAO‐B), is rapidly absorbed from the gastrointestinal tract and distributed into tissues. The reaction between MAO and selegiline takes place in two steps. The initial reversible reaction is followed by an irreversible reaction in which selegiline is bound covalently to the flavin part of the enzyme. Studies with positron emission tomography have shown retention of selegiline in brain areas with high MAO‐B activity, including striatal structures, hippocampus, thalamus, and substantia nigra. Inhibition of MAO‐B in vivo takes place rapidly; for example, platelet MAO is inhibited almost totally within the first 60 minutes after a single 10 mg oral dose of the drug. The recovery of MAO after inhibition depends on the organ and species in question. In rat brain the half‐life of recovery in the brain is approximately 8 to 12 days; in rat liver it is shorter, 1 to 3 days. Selegiline is metabolized into l‐(‐)‐desmethylselegiline, l‐(‐)‐methamphet‐amine, and l‐(‐)‐amphetamine mainly in the liver through the microsomal P‐450 system. The stereoselectivity of the metabolites is maintained; no racemic transformation takes place. All three main metabolites are found in human serum, cerebrospinal fluid, and urine, and l‐(‐)‐methamphetamine accounts for most of the metabolite pool. The metabolites are excreted mainly via urine. l‐(‐)‐Desmethylselegiline has been shown to be an irreversible inhibitor of MAO‐B in the rat and in humans. Clinical Pharmacology and Therapeutics (1994) 56, 742–749; doi:

Glyceraldehyde-3-phosphate Dehydrogenase, the Putative Target of the Antiapoptotic Compounds CGP 3466 and R-(−)-Deprenyl

“…23). The rescuing effect of (Ϫ)-deprenyl, but not that of (Ϫ)-demethyldeprenyl, in trophically withdrawn PC12 cells in vitro and in facial motor neurons after axotomy in vivo, is blocked by P450 inhibitors, and (Ϫ)-amphetamine and (Ϫ)-methamphetamine antagonize the rescuing effect of (Ϫ)-deprenyl in these paradigms (24).…”

A comparison of drug-seeking behavior maintained by d-amphetamine, l-deprenyl (selegiline), and d-deprenyl under a second-order schedule in squirrel monkeys

“…Enhanced psychomotor stimulant effects of exogenously administered β-PEA can be seen following pretreatment with l-deprenyl (Bergman et al 2001;Ortmann et al 1984;Timar and Knoll 1986). In addition to its ability to inhibit MAO-B activity and, thus, increase brain levels of dopamine and β-PEA, l-deprenyl is also metabolized to l-methamphetamine and l-amphetamine (Heinonen et al 1994;Szökö et al 1999). Plasma levels of lmethamphetamine equivalent to a dose of over 0.1 mg/kg can be achieved following chronic treatment with 1 mg/kg l-deprenyl (Schindler et al, 2003).…”

“…It is important to note that the metabolites l-methamphetamine and l-amphetamine are produced following l-deprenyl injection while the metabolites d-methamphetamine and d-amphetamine are produced following d-deprenyl injection; metabolism is stereoselective with no racemic transformation (Heinonen et al 1994;Szökö et al 1999). Given the approximately two-fold greater potency of the d-isomers of the amphetamines in behavioral studies (e.g., Winger et al, 1994;Yasar and Bergman 1994;Yokel and Pickens 1973), d-deprenyl would be more likely to be self-administered at lower doses than l-deprenyl if reinforcing efficacy is a function of the metabolites' potency.…”

l‐(−)‐Desmethylselegiline, a Metabolite of Selegiline [l‐(−)‐Deprenyl], Protects Mesencephalic Dopamine Neurons from Excitotoxicity In Vitro

“…Until recently, it has been considered that the benefits of selegiline in PD are due to its capacity to inhibit MAO-B. However, recent laboratory studies have shown that selegiline prevents neuronal degeneration in various in vivo and in vitro experimental models (Mytilineou and Cohen, 1985; Tatton and Geenwood, 1991;Salo and Tatton, 1992;Ansari et al, 1993;Roy and Bedard, 1993), through a mechanism that does not depend on inhibition ofMAO-B activity (Ansari et al, 1993;Mytilineou et al, 1997).In humans and experimental animals, selegiline is rapidly metabolized in the gastrointestinal tract and liver to L-desmethylselegiline (DMS) and L-methamphetamineby the cytochrome P-450 enzyme system (Yoshida et al, 1986;Heinonen et al, 1994;Barrett et al, 1996). DMS is an inhibitor of MAO-B, but it is less potent than selegiline in in vitro and in vivo assays (Borbe et al, 1990).…”

“…In humans and experimental animals, selegiline is rapidly metabolized in the gastrointestinal tract and liver to L-desmethylselegiline (DMS) and L-methamphetamineby the cytochrome P-450 enzyme system (Yoshida et al, 1986;Heinonen et al, 1994;Barrett et al, 1996). DMS is an inhibitor of MAO-B, but it is less potent than selegiline in in vitro and in vivo assays (Borbe et al, 1990).…”