Levodopa pharmacokinetic mechanisms and motor fluctuations in Parkinson's disease

Abstract

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.

Comparison of pharmacokinetic profile of levodopa throughout the day between levodopa/carbidopa/entacapone and levodopa/carbidopa when administered four or five times daily

“…This was especially true for relative differences between the two levodopa formulations, but also the absolute levodopa plasma levels in groups I and II were close to each other between healthy volunteers and PD patients. This adds to the previous literature reporting that there are generally no differences in PK of levodopa between de novo PD patients, patients with wearing-off symptoms, or patients with late-stage disease [22].…”

Surgical Management of Parkinson's Disease: Update and Review

“…In the early stage of the disease most symptoms can be well controlled by L-DOPA, but with its continuous usage multiple motor side effects develop, which include the end-ofdose 'wearing off' phenomenon, Levodopa-induced-dyskinesia(LID), "on-off" fluctuation, involuntary movements, neuropsychiatric phenomena, and sensory symptoms, etc. [1][2][3][4] . Since medical therapy fails to provide good, longlasting relief of symptoms, interest in the surgical treatment of PD has been rekindled.…”

Evolution of motor fluctuations in Parkinson's disease: A longitudinal study over 6 years

“…1,2 Yet, these studies may not provide a true picture of the changes of response to L-dopa that evolve over time. A group of patients selected within a year or 2 of disease onset will be representative enough, but patients whose symptoms fluctuate 10 years after diagnosis are selected from a much smaller group of surviving patients.…”