Pharmacodynamic and Pharmacokinetic Features of Cabergoline

Abstract

The appearance of late motor complications is the major drawback of long term levodopa therapy in patients with Parkinson’s disease. Although disease progression may be a factor in the aetiology of these complications, unfavourable properties of levodopa may promote their development. These include competition with amino acids for gastrointestinal absorption and passage through the blood-brain barrier; and a short duration of action with a rapid peak plasma concentration and rapid clearance, producing strong receptor stimulation that rapidly alternates with neurotransmitter vacancy and nonselective stimulation of all dopamine receptors. Moreover, advanced neurodegeneration results in loss of the anatomical substrate responsible for dopamine uptake and transport, whereas the postsynaptic dopamine receptors (the therapeutic target of dopamine agonists) are relatively spared. In theory, long-acting direct dopamine D₂ receptor agonists that also stimulate the D₁ receptor should provide a satisfactory alternative to levodopa without the above-mentioned drawbacks. Cabergoline possesses all the prerequisites for testing the hypothesis that steady stimulation of D₂ receptors may be able to minimise the development of late motor complications in patients with Parkinson’s disease. It has an appropriate receptor affinity profile, with potent and long-lasting dopaminergic stimulatory effects in 6-hydroxydopamine-lesioned rats and in MPTP (l-methyl-4-phenyl-l,2,5,6-tetrahydropyridine)-lesioned primates; it has a consistent pharmacokinetic profile, with a very long mean plasma elimination half-life of 65 to 110 hours, and its absorption and excretion are unaffected by food, age or renal or hepatic disease; moreover, when given concomitantly, cabergoline does not influence levodopa pharmacokinetics. Initial clinical studies have demonstrated that the efficacy of cabergoline is comparable to that of levodopa in patients with Parkinson’s disease. The preliminary results of a long term study of initiation of treatment with cabergoline or levodopa in patients with Parkinson’s disease are in keeping with the hypothesis that steady receptor stimulation diminishes late motor complications.