The Effect of Dosing Regimen and Food on the Bioavailability of the Extensively Metabolized, Highly Variable Drug Eldepryl([reg]) (Selegiline Hydrochloride)
Barrett JS, Rohatagi S, DeWitt KE, Morales RJ, DiSanto AR.
Am J Ther 1996 Apr;3(4):298-313


The pharmacokinetics of oral selegiline hydrochloride were examined in two crossover studies in healthy volunteers: a 5-mg b.i.d. administration in the fed-versus-fasted state and a 5-mg b.i.d. versus 10-mg q.d. multiple-dose administration. Food increased the systemic exposure of selegiline, while metabolite levels (N-desmethylselegiline, L-amphetamine and L-methamphetamine) were unaffected. Mean selegiline C(max) and AUC(t) increased by threefold in the fed state. Following multiple doses, selegiline and metabolites accumulate from single-dose exposure. The extent of accumulation was greatest for selegiline. Trough levels of 3.3 and 6.0 ng / mL for L-amphetamine and L-methamphetamine suggest that steady state was achieved by the third dosing day for these metabolites. The mean half-life of selegiline and N-desmethylselegiline of 8.6 and 9.5 h, respectively, was substantially longer than that obtained in single-dose experiments (1.5 and 3.8 h, respectively). Once- and twice-daily regimens were not equivalent with respect to selegiline pharmacokinetics. While minor differences in N-desmethylselegiline pharmacokinetics was observed, L-amphetamine and L-methamphetamine pharmacokinetics were unaffected by dosing regimen. Pharmacokinetic parameters describing selegiline plasma levels from a single 10-mg dose did not predict the plasma concentrations obtained from 5-mg b.i.d. dosing. The effects of food and regimen on selegiline pharmacokinetics are consistent with highly extracted compounds in which absorption or metabolism is site specific. These factors contribute to the high variability in selegiline plasma levels following oral dosing. The prolonged half-lives of selegiline and N-desmethylselegiline with multiple dosing may be the result of binding to the mitochondrial monoamine oxidase type B pool. Given the lack of correlation of the selegiline plasma profile following twice-daily administration with single-dose data, the assessment of bioavailability and meaningful relationships between selegiline plasma levels and pharmacologic response is best studied in a twice-daily, multiple-dose setting.
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