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 inc reases the dopamine levels in the substantia nigra. Selegiline also bl ocks dopamine re-uptake from the synaptic cleft, thus increasing the d opamine concentrations in the brain. At a dose of 10 mg/day, selegilin e is devoid of 'cheese effect'. The pharmacokinetics of selegiline are highly variable, Following an oral dose of selegiline 10mg, it is rap idly absorbed and metabolised to desmethylselegiline, levoamphetamine and levomethamphetamine, The mean peak plasma concentration (C-max) is approximately 2 mu g/L and the time to reach the peak is under an hou r. The absolute bioavailability of selegiline is approximately 10%. It has an apparent volume of distribution of 1854L. The oral clearance o f selegiline (59 L/min) is many fold higher than the liver blood flow (1.5 L/min), indicating that extrahepatic processes are involved in th e elimination of selegiline, The elimination half-life of selegiline i s about 1.5 hours. Following multiple administration of selegiline 10 mg/day, the accumulation of both the parent compound and its metabolit es have been reported. At least a 4-fold increase in the half-lives of selegiline and desmethylselegiline has been reported. There is at lea st a 3-fold increase in the C-max and area under the concentration-tim e curve of selegiline with food. One of the metabolites of selegiline, desmethylselegiline, is believed to posses some MAO-B inhibitory prop erty, though to a lesser extent than that of selegiline. Within 2 to 4 hours of an oral dose of selegiline 10mg, 86% of the platelet MAO-B a ctivity was inhibited and it took almost 2 weeks for platelet MAO-B ac tivity to return to the baseline values. Transdermal administration of selegiline resulted in an increase in the plasma concentrations of se legiline and a decrease in the formation of its metabolites, indicatin g that the extensive first-pass effect is avoided when selegiline is g iven transdermally.