Selegiline is a selective, irreversible inhibitor of MAO-B, used in the treatment of Parkinson's disease, either alone or as an adjunct to L-DOPA. The sole recommended dosing regimen is 5 mg given in the morning and at noon with breakfast and lunch. A pulsatile oral dosage form was developed to mimic the conventional tablet release from two oral administrations separated by 4 h, to permit once-daily dosing and increase compliance. The pharmacokinetics of the pulsatile delivery system was studied in six healthy male volunteers. The plasma concentration±time pro®le from the pulsatile system of selegiline and metabolites is dissimilar to that obtained from the 5 mg bid administration of the conventional tablet and cannot be considered to be bioequivalent. The initial pulse of the delivery system is rapidly absorbed but to a lesser extent than the conventional regimen; the second pulse exhibits absorption which is delayed and prolonged. The decrease in the selegiline concentration may be due to the less absorptive surface of the lower GI tract which is available to the second pulse. Another reason could be the disparity between the in vitro and in vivo release pro®les from the second pulse. Compartmental analysis indicates that the ratio of formation±absorption rate constant for the selegiline to N-desmethylselegiline pathway decreases from 1´57+1´04 for the ®rst pulse to 0´61+0´54 for the second pulse of the pulsatile delivery system, suggesting that the upper portion of the GI tract has a greater capacity to convert selegiline to N-desmethylselegiline than the lower GI tract. The lack of in vivo and in vitro correlation is most likely due to site speci®c absorption/metabolism. Regimen has been previously shown to be a signi®cant factor in estimating the extent of selegiline and metabolite exposure following oral administration. The inequivalence of dosing regimens of the same total daily dose may ultimately be linked to the saturability of gut wall metabolism. This phenomenon may preclude the development of novel delivery systems designed to mimic the recommended dosing regimen of the conventional Eldepryl 1 tablet.