A regression analytical model of serum levodopa metabolic profile in Parkinson's disease

Although levodopa and its metabolites in blood have been investigated in parkinsonian disorders for biomarkers, medication effects of levodopa-associated drugs remain unclear. In this study, we investigated levodopa associated metabolites to characterize their associations with medication and clinical symptoms in PD patients. Comprehensive metabolome analysis using plasma from PD and controls was performed in two independent cohorts previously published (PD: 109, controls: 32; PD: 145, controls: 45). To verify and analyze levodopa metabolism more precisely, we prepared another cohort [251 PD patients (16 de novo, 17 receiving only dopamine-receptor agonists, 218 receiving levodopa/benserazide or levodopa/carbidopa with/without other parkinsonian drugs) and 40 age-matched controls]. Serum levels of levodopa and its six metabolites were examined by liquid chromatography-mass spectrometry. The association of each metabolite with clinical parameters, medication, and enzymic genotypes was investigated. Serum levels of levodopa and five of its metabolites were significantly increased in PD patients administered levodopa and 4 of 5 were related to the levodopa dose. Levodopa levels were effectively maintained in PD patients given levodopa/benserazide as well as levodopa/carbidopa. However, suboptimal preservation of levodopa levels in some patients treated with levodopa/carbidopa may reflect incomplete inhibition of AADC by carbidopa. Especially when levodopa taken with entacapone, levodopa levels were significantly preserved in PD patients with levodopa/benserazide. 3-methoxytyramine level was efficiently predicted with a numerical model using levodopa, entacapone, and selegiline doses as variables, indicative of its application for drug efficacy monitoring. By using Akaike's Information Criterion for variable selection, the concentration of 3-methoxytyramine can be expressed linearly by the dosage of l-dopa, entacapone, and selegiline.