Pharmacodynamics. The mechanisms of selegiline's beneficial adjunctive action in the treatment of Parkinson disease are not fully understood, but the following explanations are offered, most of which emphasize its role as a neuroprotective agent:
| • The efficacy of selegiline was initially attributed to a neuroprotective effect by inhibition of monoamine oxidase type B activity. Most of the neuroprotective effects occur independently of selegiline's efficacy to inhibit monoamine oxidase type B activity. These include protection of neurons against neurotoxins, stimulation of gene expression of L-aromatic amino acid decarboxylase, increase in striatal phenylethylamine levels, and activation of dopamine receptors. Selegiline might contribute to neuroprotection in Parkinsonian patients by enhancing brain-derived neurotrophic factor (14). Preclinical studies have shown that neuroprotective and antiapoptotic effects of selegiline are linked to its propargylamide structure, which it shares with rasagiline, another drug with similar properties (Szoko et al 2018). |
| • Selegiline may increase dopaminergic activity by other mechanisms, including interfering with dopamine reuptake at the synapse. Selegiline reduces the turnover of dopamine; therefore, selegiline has been considered to reduce free radical formation and, thus, act as a neuroprotective agent. |
| • Effects resulting from selegiline administration may also be mediated through its metabolites. Two of its three principal metabolites, (1) amphetamine and (2) methamphetamine, have pharmacological actions of their own; they interfere with neuronal uptake and enhance the release of several neurotransmitters (eg, norepinephrine, dopamine, serotonin); however, the extent to which these metabolites contribute to the effects of selegiline is unknown. |
| • The beneficial effect of selegiline has been attributed to neuroprotection via inhibition of apoptosis. |
| • Neuroprotective effect prevents progression in Parkinson disease by increases in production of neurotrophins, such as nerve growth factor, brain-derived neurotrophic factor, and glial cell line-derived neurotrophic factor, that protect neurons from the inflammatory processes. |
| • Experimental studies suggest that c-Jun-N terminal kinase pathways are involved in oxidative stress-induced dopaminergic neuronal degeneration, and pretreatment with selegiline affords neuroprotection by inhibiting these cell death-signaling pathways. |
| • Selegiline delays the nucleation phase of alpha-synuclein aggregation, leading to the formation of nontoxic species, a beneficial effect in Parkinson disease. |
Pharmacokinetics. Important points of various pharmacokinetic studies are as follows:
| • Following the oral administration of a single dose of 10 mg of selegiline hydrochloride to human subjects, serum levels of intact selegiline were below the limit of detection. |
| • Three metabolites were found in serum and urine, and these include (1) N-desmethyldeprenyl, the major metabolite (mean half-life 2.0 hours); (2) amphetamine (mean half-life 17.7 hours); and (3) methamphetamine (mean half-life 20.5 hours). Over a period of 48 hours, 45% of the dose administered appeared in the urine as these three metabolites. |
| • Following a 10 mg daily dose of selegiline hydrochloride for 7 consecutive days, the mean trough serum levels are 3.5 ng/mL for amphetamine and 8.0 ng/mL for methamphetamine, whereas trough levels of N-desmethyldeprenyl are below the levels of detection. |
| • The rate of monoamine oxidase type B regeneration following discontinuation of treatment has not been quantified. |
Formulations and methods of delivery. Two special methods of delivery are transdermal and fast-dissolving oral formulation.
Transdermal. The selegiline transdermal system has novel pharmacokinetic and pharmacodynamic properties. Compared with oral administration, transdermal selegiline leads to sustained plasma concentrations of the parent compound, increasing the amount of drug delivered to the brain and decreasing metabolite production, thereby reducing the risk of interactions with tyramine-rich foods. A selegiline transdermal system, Emsam®, approved by the United States Food and Drug Administration, has unique pharmacokinetic and pharmacodynamic properties that allow inhibition of central nervous system MAO-A and MAO-B enzymes while substantially avoiding inhibition of intestinal and liver MAO-A enzyme (20). Administration of selegiline by this method results in an increase in the plasma concentrations of selegiline and a decrease in the formation of its metabolites, indicating that the extensive first-pass effect is avoided when selegiline is given transdermally. This novel transdermal system provides targeted MAO inhibition and avoids the need for dietary restrictions at the minimum effective dose of 6 mg/24 hours, but the precaution is necessary at higher doses of the 9-mg or 12-mg patches. Clinical trials and postmarketing studies of transdermal selegiline have established that doses between 6 and 12 mg over 24 hours are well tolerated and effective for major depressive disorder (01).
Results of an experimental study show that therapeutic amounts of selegiline can be easily delivered by transdermal iontophoresis with simple gel patches of modest surface area (07).
Fast-dissolving oral formulation. A fast-dissolving formulation of selegiline avoids first-pass metabolism and has been shown to improve efficacy and tolerability. Zydis selegiline has been shown to be a safe and effective therapy for Parkinson disease with motor fluctuations and wearing off. One double-blind, placebo-controlled, parallel-design trial of fast-dissolving selegiline formulation Zelapar showed no significant difference in improvement in percentage of off time as compared to placebo, but combined analysis with a parallel study that showed a significant improvement in off time with selegiline suggested overall efficacy. An orally disintegrating tablet is suitable for patients who report adverse events after initial treatment with conventional selegiline or who suffer from swallowing difficulties.
Selegiline nasal gel. To enhance the bioavailability and concentration of selegiline in the brain, a mucoadhesive nasal thermosensitive gel (SNT-gel) was prepared using Poloxamer 407-Chitosan combination and tested in rats (18). Results showed a significant increase in brain dopamine, a reduction in monoamine oxidase B level, and an increase in catalase activity and level of reduced glutathione following treatment with SNT-gel, indicating its effectiveness, which was also supported by histopathology examination of brain tissues.
Drug monitoring. Metabolites of selegiline include l-methamphetamine, l-amphetamine, and desmethylselegiline, which is highly addictive psychostimulant and one of the most abused drugs. In order to differentiate medical selegiline users form illicit methamphetamine abusers, it is important to distinguish between the l-isomers and d-isomers in urine samples. The urine sample is screened using headspace-solid phase microextraction-gas chromatography-mass spectrometry, which detects both methamphetamine and amphetamine in addition to selegiline and desmethylselegiline. To quantitate methamphetamine and amphetamine, a standard addition method shows that the ratio of amphetamine to methamphetamine is 0.27, which is in the range of selegiline ingestion (17).
