Pharmacokinetic and pharmacodynamic mechanisms for levodopa have been studied in 
relation to the pathogenesis of the motor fluctuations which complicate advanced 
Parkinson's disease. Since levodopa clearance from the general circulation was 
found to be similar in patients with wearing-off or on-off phenomena and those 
with a stable response to levodopa, peripheral pharmacokinetic factors are 
unlikely to be involved. Efficacy half-time for levodopa, on the other hand, was 
significantly reduced in patients with mainly wearing-off fluctuations in 
comparison to those manifesting a stable response to oral levodopa; individuals 
with predominantly on-off phenomenon had an even more extreme reduction in the 
duration of the antiparkinsonian action of levodopa. Conversion from oral to 
intravenous levodopa treatment immediately stabilized plasma levodopa levels in 
both the wearing-off and on-off groups; motor variability also decreased, 
especially in those with wearing-off phenomenon. During 11 days of continuous 
intravenous levodopa therapy, additional reductions in motor fluctuations 
occurred in both groups, but at a significantly faster rate in patients with 
wearing-off than in those with on-off responses. These results suggest that 
wearing-off phenomenon may arise as a consequence of the degeneration of 
dopamine terminals due to natural disease progression with a resultant inability 
to buffer variations in levodopa availability; on-off phenomenon, may reflect 
additional postsynaptic dopamine receptor dysregulation, possibly in response to 
the resultant, nonphysiologic fluctuations in synaptic dopamine.