PERIPHERAL AND CENTRAL PHARMACOKINETICS OF APOMORPHINE AND ITS EFFECTON DOPAMINE METABOLISM IN HUMANS

Apomorphine is a dopamine receptor agonist increasingly used in the tr eatment of Parkinson's disease (PD). In the present study, we examined the plasma and ventricular cerebrospinal fluid (CSF) pharmacokinetics of apomorphine as well as its effects on dopamine metabolism in six p atients (one woman and five men, mean age 79.5 years) without evidence of PD who underwent 48-h intracranial pressure monitoring for suspect ed normal pressure hydrocephalus. Maximal plasma apomorphine concentra tion (25.04 ng/ml) is found 20 min after subcutaneous injection (50 mu g/kg), and the mean area under the curve is 1,439.37 ng/ml for 120 mi n. In contrast to plasma values, the maximal ventricular CSF apomorphi ne concentration (1.08 ng/ml) is found 30 min after injection and the mean area under that curve is 7% of that of plasma (96.69 ng/ml for 12 0 min). Apomorphine administration causes a significant reduction in v entricular CSF concentrations of dopamine and of its major metabolites sulfoconjugated dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA). This effect starts 10 min after the injectio n of apomorphine, is maximal after 30 min (free dopamine, -30%; sulfoc onjugated dopamine, - 28%; HVA, -21%; DOPAC, - 31%) and is still prese nt, although to a lesser extent (-5 to - 10%), 120 min after the injec tion of apomorphine. This study shows that in humans a dose of apomorp hine commonly used in PD causes significant inhibition of dopamine met abolism lasting >120 min. In addition to their symptomatic effects, do pamine agonists such as apomorphine may play a role in preventing or s lowing the neurodegeneration in PD by autoreceptor-mediated inhibition of dopamine metabolism.