The On–Off Phenomenon in Parkinson's Disease: Relation to Levodopa Absorption and Transport

To determine whether the oscillating clinical response to levodopa in Parkinson's disease (the “on–off” phenomenon) reflects fluctuations in absorption and transport of the drug, we investigated this phenomenon in nine patients with an oscillating motor state. We studied the response to continuous infusion of levodopa and the effects of meals on the plasma levodopa concentrations and on the clinical response during oral and intravenous administration of the drug. Meals reduced peak plasma levodopa concentrations by 29 percent and delayed absorption by 34 minutes. Bypassing absorption by constant infusion of the drug produced a stable clinical state lasting for 12 hours in all of six patients and for up to 36 hours in some. High-protein meals or oral phenylalanine, leucine, or isoleucine (100 mg per kilogram of body weight) reversed the therapeutic effect of infused levodopa without reducing plasma levodopa concentrations. Glycine and lysine at identical doses had no effect. We conclude that interference with absorption of levodopa by food and by competition between large neutral amino acids and levodopa for transport from plasma to the brain may be partly responsible for the fluctuating clinical response in patients with Parkinson's disease. (N Engl J Med 1984; 310:483–8.).