The contribution of the peripheral and central pharmacokinetic mechanisms of 
levodopa to the pathogenesis of the motor fluctuations that complicate its 
long-term administration was studied in 28 parkinsonian patients. The rate of 
levodopa clearance from the general circulation, its plasma half-life, and 
apparent volume of distribution were indistinguishable between patients with the 
on-off or the wearing-off phenomenon and those with a stable response to 
levodopa or those who had not been previously treated with levodopa. Peripheral 
pharmacokinetic factors are thus unlikely to account for the development of 
these response fluctuations. Conversely, the efficacy half-time of levodopa 
differed markedly among the four response groups studied and may provide a 
quantitative index of central mechanisms that favor the development of the 
wearing-off and on-off phenomena. Although symptom duration was the best 
predictor of the severity of untreated parkinsonism, levodopa dose correlated 
best with response half-time. The wearing-off phenomenon may primarily reflect 
the loss of buffering capacity caused by degeneration of the dopamine neurons, 
while the development of the on-off phenomenon appears to require additional 
postsynaptic changes, possibly at the receptor level.