CONCENTRATION-EFFECT RELATIONSHIP OF LEVODOPA IN PATIENTS WITH PARKINSONS-DISEASE

Studies on the concentration-effect relationship of levodopa in Parkin son's disease have established that: (1) in patients with a fluctuatin g response to levodopa, concentration-effect profiles are steeper and markedly shifted to the right (i.e, potency is decreased) compared wit h those patients whose symptoms are adequately controlled; (2) with co ntrolled-release (CR) preparations, the concentration-effect relations hip indicates a decreased potency compared with conventional immediate -release (IR) preparations; and (3) coadministration of a dopamine rec eptor agonist (even at a subclinical dose) enhances the potency of lev odopa, These findings support some current hypotheses on the origin of , and the pathophysiological process underlying, response fluctuations . In patients with response fluctuations, metabolism of levodopa and s torage of dopamine in the striatum are reduced. Levodopa is decarboxyl ated in the extracellular space, with the result that dopamine is rele ased directly to the effect site. Thus, without dopamine storage actin g as a buffer between levodopa metabolism and dopaminergic effect, the decline in motor response closely follows the decrease in levodopa co ncentrations, Even small fluctuations of levodopa concentrations aroun d the EC(50) value (the concentration threshold necessary to produce a motor response) might be followed by response fluctuations. Patients with Parkinson's disease who do not have response fluctuations exhibit a residual capacity of production and storage of endogenous dopamine; thus, lower amounts of 'exogenous' dopamine (formed by decarboxylatio n of levodopa) are required. The storage buffer is responsible for a t ime lag between decline in peripheral plasma concentrations of levodop a and dopamine-induced motor response. Low doses of a dopamine recepto r agonist increase the basal tonus of the striatum, but do not reach t he threshold concentration for triggering a motor response. Because of the dichotomic character of the motor response, patients do not switc h from an 'off' (not responding) phase to an 'on' (responding) phase. However, lower amounts of exogenous dopamine released in the synaptic cleft will be necessary to induce response. To date, pharmacokinetic-p harmacodynamic modelling does not give a clear answer as to whether re sponse fluctuations are additionally induced by receptor desensitisati on or inhibition of the active transport of levodopa across the blood- brain barrier by the main metabolite of levodopa, 3-O-methyldopa. Neve rtheless, there is some evidence that higher plasma concentrations of levodopa are required for similar motor effects when CR preparations a re compared with IR preparations. Attempts have been made to establish therapeutic drug monitoring of levodopa in patients with response flu ctuations. The interindividual variability of EC(50) values in single studies is relatively low (10% to a maximum of 50%), which might allow specification of a 'population' threshold plasma concentration (i.e. a minimal effective plasma concentration required to obtain clinical e ffects). However, considering the short elimination half-life of levod opa, it seems doubtful whether such target drug concentrations can be maintained as steady-state. A marked prolongation of the dosage interv al with CR preparations might be limited by the higher threshold conce ntrations of levodopa necessary to maintain clinical effects.