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Pharmacodynamic modeling of oral levodopa

Clinical application in Parkinson's disease

Institute of Neurology, University of Bologna, Bologna, Italy.

We investigated the relationship between levodopa plasma concentration and the tapping effect, after a standard oral levodopa test, by kinetic-dynamic modeling in 40 parkinsonian patients with stable or fluctuating response to levodopa, and found no difference in levodopa plasma pharmacokinetics between stable and fluctuating patients. Conversely, levodopa equilibration half-life between plasma and effect-site concentration was fivefold shorter on average in fluctuating patients. Overall, levodopa equilibration half-life highly correlated with the duration of tapping response and provided a reliable quantitative index of central mechanisms that affect the length of clinical effect. Individual fitting of tapping measures to modeled drug effect-site concentrations by sigmoid E_max model revealed that fluctuating patients required almost two-fold higher levodopa concentrations (EC₅₀) to elicit almost the same motor response (E_max). These findings suggest that shortening of levodopa clinical effect may be accompanied by a reduced drug affinity for the nigrostriatal dopaminergic system (EC₅₀), with no change in its intrinsic activity (E_max).

Address correspondence and reprint requests to Dr. Manuela Contin, Institute of Neurology, Via U. Foscolo 7, 40123 Bologna, Italy.

This work was part of the "Progetto Finalizzato Invecchiamento" of the National Research Council of Italy, grant no. 922186.

Presented in part at the 2nd International Congress of Movement Disorders, Munich, Germany, June 24–26, 1992.

Received April 20, 1992. Accepted for publication in final form July 7, 1992.

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