The pharmacology of selegiline pertains to the pharmacodynamic and pharmacokinetic properties of the antiparkinsonian and antidepressant selegiline (L-deprenyl). Selegiline is available in a few different forms, including oral tablets and capsules, orally disintegrating tablets (ODTs), and transdermal patches. These forms have differing pharmacological properties.
In terms of pharmacodynamics, selegiline acts as a monoamine oxidase (MAO) inhibitor. It is a selective inhibitor of monoamine oxidase B (MAO-B) at lower doses but additionally inhibits monoamine oxidase A (MAO-A) at higher doses. MAO-B inhibition is thought to result in increased levels of dopamine and β-phenethylamine, whereas MAO-A inhibition results in increased levels of serotonin, norepinephrine, and dopamine. Selegiline is also a catecholaminergic activity enhancer (CAE) and enhances the action potential-evoked release of norepinephrine and dopamine. Through its active metabolites levomethamphetamine and levoamphetamine, selegiline acts as a weak norepinephrine and/or dopamine releasing agent. The clinical significance of this action is unclear, but it may be relevant to the effects and side effects of selegiline, especially at higher doses.
With regard to pharmacokinetics, the bioavailability of the oral form is 4 to 10%, of the ODT is 5 to 8times that of the oral form, and of the transdermal patch is 75%. The plasma protein binding of selegiline is 85 to 90%. It is metabolized extensively in the liver by the cytochrome P450 enzyme CYP2B6 among other enzymes. Metabolites of selegiline include desmethylselegiline (DMS), levomethamphetamine, and levoamphetamine. The oral form of selegiline is subject to strong first-pass metabolism and levels of the metabolites of selegiline are much lower with the ODT and transdermal patch forms than with the oral form. The elimination half-lives of selegiline and its metabolites range from 1.2 to 10hours for selegiline, 2.2 to 9.5hours for DMS, 14 to 21hours for levomethamphetamine, and 16 to 18hours for levoamphetamine. Selegiline and its metabolites are eliminated mainly in urine, with its metabolites accounting for the vast majority of eliminated material in the case of the oral form.
Pharmacodynamics Monoamine oxidase inhibitor Selegiline acts as an inhibitor of the enzyme monoamine oxidase (MAO) and hence is known as a monoamine oxidase inhibitor (MAOI). There are two types of MAO, MAO-A and MAO-B. MAO-A metabolizes the monoamine neurotransmitters serotonin, dopamine, and norepinephrine as well as trace amines like tyramine, whereas MAO-B metabolizes dopamine and the trace amine β-phenethylamine. At lower concentrations and at typical clinical doses (≤10mg/day), selegiline selectively inhibits MAO-B. Conversely, at higher concentrations and doses (≥20mg/day), selegiline additionally inhibits MAO-A. By selectively inhibiting MAO-B, selegiline increases levels of dopamine in the brain and thereby increases dopaminergic neurotransmission. At higher doses, by inhibiting both MAO-A and MAO-B, selegiline increases brain levels of serotonin, dopamine, and norepinephrine and thereby increases serotonergic, dopaminergic, and noradrenergic neurotransmission. Selegiline is an irreversible mechanism-based inhibitor (suicide inhibitor) of MAO that acts by covalently binding to the active site of the enzyme and thereby disabling it. Selegiline is thought to exert its therapeutic effects in the treatment of the motor symptoms of Parkinson's disease by increasing dopamine levels in the substantia nigra pars compacta (SNpc) of the basal ganglia, which projects to the caudate nucleus and putamen of the striatum, thereby enhancing the signaling of the nigrostriatal pathway. In addition to the nigrostriatal pathway, selegiline may also influence and potentiate other dopaminergic pathways and areas, including the mesolimbic pathway, mesocortical pathway, tuberoinfundibular pathway, and chemoreceptor trigger zone, which may also be involved in its effects as well as side effects. Selegiline and other MAO-B inhibitors may additionally improve non-motor symptoms in Parkinson's disease, for instance depression and motivational deficits, by increasing dopamine levels. Selegiline may have some disease-modifying neuroprotective effects in Parkinson's disease by inhibiting the MAO-B-mediated oxidation of dopamine into reactive oxygen species that damage dopaminergic neurons in the nigrostriatal pathway via oxidative stress. However, the pathophysiology of Parkinson's disease is complex and multifacted, and MAO-B inhibitors may only slow the progression of the disease and do not halt it.
The MAO-B inhibition by oral selegiline shows dosage dependence at typical therapeutic doses and below (i.e., ≤10mg/day). Selegiline almost completely inhibits MAO-B in blood platelets at an oral dosage of 10mg/day. Following a single 5 or 10mg oral dose of selegiline, 86 to 90% of MAO-B activity in platelets was inhibited within 2 to 4hours and 98% of activity was inhibited after 24hours. MAO-B inhibition with lower doses of selegiline has also been assessed. A dosage of oral selegiline of 1mg/day for 10days inhibited platelet MAO-B activity by about 75 to 100% in 3individuals. In another study, a single oral dose of selegiline was found to maximally inhibit platelet MAO-B activity by 23% at 0.5mg, 40% at 1.0mg, 52% at 1.5mg, 85% at 5mg, and 96% at 10mg and with maximal inhibition occurring after 0.5 to 0.8hours. For comparison, a single 0.5mg dose by intravenous injection maximally inhibited platelet MAO-B activity by 80 ± 15% in the same study and this occurred within 5minutes. Using a logistic model, it was estimated that a 3.4mg oral dose of selegiline would be equivalent to 0.5mg intravenously (an 85% or 7:1 lower dose) in terms of MAO-B inhibition. In people with Parkinson's disease, selegiline at dosages of 10mg/day, 5mg/day, 10mg twice weekly (or 20mg/week), and 10mg once a week resulted in greater than 95% inhibition of platelet MAO-B activity within 1week with all dosages except the 10mg weekly dose. The specific degrees of inhibition after 4weeks were 99.4% with 10mg/day, 99.5% with 5mg/day, 96.0% with 10mg twice per week, and 75.9% with 10mg once per week, respectively. On the basis of these findings, it was concluded that 20mg per week (as 10mg twice per week) is the minimum dosage that can produce maximal and long-lasting inhibition of platelet MAO-B activity. There is considerable (>5-fold) accumulation of selegiline with daily repeated administration, which may increase its potency in terms of MAO-B inhibition relative to single doses.
Following a single 5 or 10mg oral dose of selegiline, inhibition of platelet MAO-B activity persisted at above 90% for 5days and almost 14days were required before activity returned to baseline. Besides the degree of inhibition of MAO-B, the time for MAO-B activity to return to baseline also shows dosage dependence. Platelet MAO-B activity returned to normal within 24hours with a single 0.5mg oral dose, whereas 1week was required for single 1.0 and 1.5mg oral doses and 2weeks were required after single 10mg oral or 0.5mg intravenous doses.
The recommended dosing schedule of selegiline in Parkinson's disease (10mg/day) has been described as somewhat questionable and potentially excessive from a pharmacological standpoint. Selegiline has been predicted to inhibit platelet MAO-B activity by approximately 95% or more after 96hours with 2.5mg/day, after 48hours with 5.0 or 7.5mg/day, and within 24hours with a single 10mg dose. Following this however, it is predicted that there will be a plateau and complete or near-complete MAO-B inhibition regardless of whether the dosage is 2.5 or 10mg/day. Relatedly, researchers have called for lower doses of selegiline, like 2.5 or 5mg/day or 10mg twice per week (20mg/week total), to be evaluated in clinical trials. It has been suggested that lower doses of selegiline could be equally effective in terms of MAO-B inhibition as conventional doses and potentially in terms of clinical effectiveness. However, per some researchers, optimal effectiveness of selegiline in Parkinson's disease seems to require a dosage of 10mg/day and its effectiveness lasts only about 2 to 3days following discontinuation. On the other hand, another study found that 5mg/day produced the same benefit as 10mg/day in people with Parkinson's disease.
Peripheral and brain MAO-B are assumed to be inhibited with selegiline to similar extents. Accordingly, selegiline at an MAO-B-selective dosage of 10mg/day has been found to inhibit brain MAO-B by more than 90% in postmortem individuals with Parkinson's disease. This dosage of selegiline has been found in such individuals to produce increases in brain levels of dopamine of 23 to 350% and of β-phenethylamine of 1,200 to 3,400% depending on the brain area and the study. Brain MAO-B levels recover slowly upon discontinuation of selegiline, with a half-time of brain MAO-B synthesis and recovery of approximately 40days in humans.
Selegiline inhibits MAO-B by 50% at a very low concentration of 26pg/mL in vivo, indicating that it is a very potent MAO-B inhibitor. It is about 500 to 1,000times more potent in inhibiting MAO-B than MAO-A in vitro and about 100times more potent in vivo in rodents. The clinical selectivity of selegiline for MAO-B is lost at oral doses of the drug above 20mg/day. In a study of post-mortem individuals who were on selegiline 10mg/day, MAO-A activity in the brain was inhibited by 38 to 86%. A more recent study using positron emission tomography (PET) imaging similarly found inhibition of brain MAO-A by 33 to 70% in humans. However, while brain dopamine and β-phenethylamine levels are substantially increased at this dosage, brain levels of serotonin and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) remain unchanged. It has been found in animal studies that brain MAO-A must be inhibited by nearly 85% before serotonin, norepinephrine, or dopamine levels increase and result in increased functional activity as well as accompanying behavioral changes. Selegiline at an oral dosage of 10mg/day does not cause the "cheese effect" as assessed by oral tyramine and β-phenethylamine challenge tests. These findings indicate that selegiline does not importantly inhibit MAO-A at a dosage of 10mg/day. However, a dosage of 20mg/day selegiline did increase the pressor effect of tyramine, indicating that doses this high and above can significantly inhibit MAO-A. The "cheese reaction" is known to be specifically dependent on inhibition of intestinal MAO-A.
In accordance with its MAOI activity, selegiline (30–60mg/day) has been found to decrease blood levels of 3,4-dihydroxyphenylacetic acid (DOPAC) (by >50%) and 3,4-dihydroxyphenylglycol (DHPG) (by >65%), the main terminal metabolites of dopamine and norepinephrine, respectively. Conversely, circulating levels of norepinephrine and epinephrine, as well as L-DOPA, were not significantly affected in the study.