Pharmacokinetic and pharmacodynamic considerations in management of motor response fluctuations in Parkinson's disease.

Recent advances in the understanding of the pharmacokinetics of levodopa and other anti-Parkinson agents have brought about the development of rational approaches to the management of levodopa-related fluctuations in motor performance that plague the majority of patients with advanced PD. The rapid systemic clearance of levodopa underlies the "short duration" response to the drug, which is progressively unmasked as PD progresses and central dopamine synthetic and storage capacity can no longer buffer fluctuations in plasma levodopa levels. Dyskinesias may be considered a secondary pharmacodynamic consequence of such pharmacokinetically induced oscillations in brain dopamine levels. Therapeutic approaches aimed at stabilizing brain dopaminergic activity include the use of slowly releasing galenic formulations of levodopa, synthetic dopamine agonists of long-lasting biologic activity, and drugs such as deprenyl that act as "dopamine extenders." It remains to be seen whether early use of such treatment approaches will reduce the prevalence of motor response fluctuations, which are one of the most disabling complications of long-term treatment of PD.