ABSORPTION AND PRESYSTEMIC METABOLISM OF SELEGILINE HYDROCHLORIDE AT DIFFERENT REGIONS IN THE GASTROINTESTINAL-TRACT IN HEALTHY-MALES

Purpose. The absorption and disposition of selegiline (SEL) and its me tabolites N-desmethylselegiline (DMS), L-methamphetamine (MET), and L- amphetamine (AMP) were assessed in 8 healthy male volunteers at proxim al and distal regions of the intestine relative to oral administration (in the stomach) to determine if intestinal site dependence contribut ed to the erratic oral absorption of selegiline hydrochloride which is manifest as low and variable bioavailability. Methods. An open-label, four-way crossover, single dose pharmacokinetic study comparing the b ioavailability of 10 mg selegiline hydrochloride administered to healt hy young males as a solution by the oral route (in the stomach) and by a nasoenteric tube to the following three sites: duodenum, jejunum an d terminal ileum was conducted. Infusions were administered over a 1 m inute interval and a two week washout was observed between treatments. Samples were taken over 96 hours and analyzed by LC/MS/MS. Results. S elegiline exposure was greatest following administration to the stomac h (similar to 150% > duodenum or jejunum) and least in the terminal il eum (similar to 33% less than duodenum or jejunum). Duodenal and jejun al sites were equivocal based on selegiline absorption and subsequent metabolism. While both AMP and MET exposure was equivalent at all dosi ng sites, DMS exposure was less (similar to 18%) at the terminal ileum . Conclusions. The oral absorption of selegiline is neither permeabili ty-limited or intestinal site-dependent. Stomach absorption may bypass presystemic metabolism. The reduced DMS exposure at the terminal ileu m is consistent with the theorized presystemic formation of DMS via lu minal P450 enzymes and the density of these enzymes in the duodenum an d jejunum relative to the ileum. AMP and MET metabolites were insensit ive to dosing site consistent with their hepatic formation. The true m agnitude of these effects would require multiple dosing as single dose pharmacokinetics do not predict the extent of multiple dose selegilin e exposure.