L-DOPA pharmacokinetics in the MPTP-lesioned macaque model of Parkinson's disease

Abstract

ObjectiveThe 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned non-human primate is widely used to model Parkinson's disease (PD) and to evaluate the efficacy of new therapies. However, some doubts have been raised about the translatability of findings in the MPTP-lesioned monkey, because the doses of l-3,4-dihydroxyphenylalanine (l-DOPA) required to alleviate parkinsonism and elicit dyskinesia are high, on a mg/kg basis, when compared to clinical practice. Thus, in the MPTP-lesioned macaque, doses ranging from 20 to 40 mg/kg might be used, while in the clinic single l-DOPA administrations ranging from 100 to 200 mg are more typical. However, bioavailability of drugs varies between species and it is unknown how plasma l-DOPA levels providing therapeutic benefit in the non-human primate compare to those having similar actions in PD patients. MethodsWe administered acute challenges of l-DOPA 30 mg/kg orally to MPTP-lesioned macaques with established dyskinesia, and determined plasma, brain and cerebrospinal fluid (CSF) levels of l-DOPA using high-performance liquid chromatography–mass spectrometry/mass spectrometry. ResultsThe maximal plasma concentration of l-DOPA (Cmax) was 18.2 ± 3.8 nmol/ml and was achieved 1.6 ± 0.3 h after administration (tmax). Half-life was 58.8 ± 22.7 min. l-DOPA levels in the caudate nucleus at peak behavioural effect were 3.3 ± 0.7 μg/g tissue protein while they were 1.5 ± 0.1 nmol/ml in the CSF. ConclusionsAlthough therapeutically-active doses of l-DOPA administered to the MPTP-lesioned macaque are higher on a mg/kg basis than those administered in clinical settings, they lead to l-DOPA Cmax similar to those achieved with 200 mg l-DOPA in clinic. l-DOPA tmax and half-life are also similar to those reported in human.