Clinical pharmacokinetics and pharmacodynamics of selegiline. An update

Selegiline is a selective inhibitor of monoamine oxidase-B (MAO-B) at a dose of 10 mg/day and is given to patients with Parkinson's disease as an adjunct to levodopa therapy. By inhibiting MAO-B, selegiline increases the dopamine levels in the substantia nigra. Selegiline also blocks dopamine re-uptake from the synaptic cleft, thus increasing the dopamine concentrations in the brain. At a dose of 10 mg/day, selegiline is devoid of 'cheese effect'. The pharmacokinetics of selegiline are highly variable. Following an oral dose of selegiline 10 mg, it is rapidly absorbed and metabolised to desmethylselegiline, levoamphetamine and levomethamphetamine. The mean peak plasma concentration (Cmax) is approximately 2 micrograms/L and the time to reach the peak is under an hour. The absolute bioavailability of selegiline is approximately 10%. It has an apparent volume of distribution of 1854 L. The oral clearance of selegiline (59 L/min) is many fold higher than the liver blood flow (1.5 L/min), indicating that extrahepatic processes are involved in the elimination of selegiline. The elimination half-life of selegiline is about 1.5 hours. Following multiple administration of selegiline 10 mg/day, the accumulation of both the parent compound and its metabolites have been reported. At least a 4-fold increase in the half-lives of selegiline and desmethylselegiline has been reported. There is at least a 3-fold increase in the Cmax and area under the concentration-time curve of selegiline with food. One of the metabolites of selegiline, desmethylselegiline, is believed to posses some MAO-B inhibitory property, though to a lesser extent than that of selegiline. Within 2 to 4 hours of an oral dose of selegiline 10 mg, 86% of the platelet MAO-B activity was inhibited and it took almost 2 weeks for platelet MAO-B activity to return to the baseline values. Transdermal administration of selegiline resulted 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.