Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Monoamine oxidase B inhibitors, ATC-code: N04BD01 Selegiline is a selective MAO-B-inhibitor which prevents dopamine breakdown in the brain. It also inhibits the reuptake of dopamine at the presynaptic dopamine receptor. These effects potentiate dopaminergic function in the brain and help to even out and prolong the effect of exogenous and endogenous dopamine. Thus, selegiline potentiates and prolongs the effect of levodopa in the treatment of parkinsonism. Since it does not interfere with the breakdown of 5 hydroxytryptamine (serotonin) or noradrenaline, it does not cause any hypertensive crises or changes in the plasma or urinary metabolites of these monoamines. Although dietary restrictions are not necessary during selegiline treatment, the inhibition of MAO B in blood platelets can lead to a slight potentiation of the circulatory effects of any tyramine not broken down by gastrointestinal MAO A during absorption.
The magnitude of increase in the urinary excretion of β phenylethylamine over 24 hours is simply related to the area under the selegiline plasma concentration-time curve after any selegiline product. Urinary β phenylethylamine increase reflects the degree of inhibition of MAO B.
Double-blind studies on early phase Parkinsonian patients showed that patients receiving selegiline monotherapy manage significantly longer without levodopa therapy than controls receiving placebo. These patients could also maintain their ability to work longer.
The addition of selegiline to levodopa (with or without decarboxylase inhibitor) therapy helps to alleviate dose related fluctuations and end of dose deterioration.
When selegiline is added to such a regimen it is possible to reduce the levodopa dosage by an average of 30%.
Unlike conventional MAO-inhibitors, which inhibit both the MAO-A and MAO-B enzyme, selegiline is a specific MAO-B inhibitor and can be given safely with levodopa.
Selegiline HCl does not cause the so called "cheese effect" either when used alone as monotherapy, or when used with other drugs, except for moclobemide or nonselective MAO-inhibitors.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties

Absorption
Selegiline HCl is readily absorbed from the gastrointestinal tract. The maximal concentrations are reached in 0.5-0.75h after oral administration in fasting state. The bioavailability is low; 10% (on the average; interindividual variation is large) of unchanged selegiline can reach the systemic circulation. Selegiline is a lipophilic, slightly basic compound which quickly penetrates into tissues, also into brain.

Distribution
Selegiline is rapidly distributed throughout the body, the apparent volume of distribution being 500 1 after an intravenous 10 mg dose. 75-85% of selegiline is bound to plasma proteins at therapeutic concentrations. Selegiline HCl inhibits enzyme MAO-B irreversibly and enzyme activity only increases again after new enzyme is synthesised.
The strong inhibitory effect platelet enzyme MAO-B activity after single 10 mg dose lasts over 24 h, and the platelet enzyme MAO-B activity returns to normal level approximately after 2 weeks.

Biotransformation
Selegiline is rapidly metabolised, mainly in the liver, into active metabolites desmethylselegiline, l-methamphetamine and to l-amphetamine, with elimination half-lives of 2.1h, 20.5 h and 17.7 h respectively. In vitro studies indicate that CYP2B6 is the main hepatic cytochrome P450 (CYP) enzyme involved in the metabolism of selegiline with a possible contribution of CYP3A4 and CYP2A6.
Selegiline AUC and desmethylselegiline AUC increase 2.7 fold and 1.5 fold respectively from day 1 to day 8 on dosing 10 mg od. However, the half-lives of selegiline (range, 1.5-3.5 h) and desmethylselegiline (range, 3.4 – 5.3 h) were found to be relatively short. Accordingly, the short half-lives of these compounds failed to predict the apparent accumulation.
The most likely explanation for the significant increase in selegiline and desmethylselegiline concentrations in serum which was observed during the 8-day multiple dose administration of selegiline HCl is saturation of MAO-B binding sties in tissues, as the rapid elimination of both selegiline and desmethyl selegiline cannot explain the apparent accumulation observed. However, decrease in the first-pass metabolism of selegiline on multiple dosing cannot be ruled out.

Elimination
In humans, the three metabolites have been identified in plasma and urine after single and multiple doses of selegiline. The mean elimination half-life is 1.5-3.5 h for selegiline. The total body clearance of selegiline is about 240 I/h. The metabolites of selegiline are excreted mainly via the urine with about 15% occurring in the faeces.