Selegiline

Pharmacology
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By K K Jain MD

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 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 3 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.
  • 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 (Chetsawang et al 2008).

Selegiline delays the nucleation phase of alpha-synuclein aggregation, leading to the formation of nontoxic species, a beneficial effect in Parkinson disease (Braga et al 2011).

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 3 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.

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 (Patkar et al 2006).

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 (Poston and Waters 2007). 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 (Ondo et al 2007). An orally disintegrating tablet is suitable for patients who report adverse events after initial treatment with conventional selegiline or who suffer from swallowing difficulties (Löhle and Storch 2008).