Causal Connection Between Serum Levodopa Metabolic Profile and Medication in Parkinson’s Disease

Abstract No methods to assess efficacy of levodopa-associated therapy by blood sampling in Parkinson’s disease (PD) have been established. 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 (PD: 109, controls: 32; PD: 145, controls: 45). In another validation 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. Significant increases in 3-methoxytyrosine and homovanillic acid were observed in PD patients administered levodopa/benserazide or levodopa/carbidopa. Serum levels of levodopa and five of its metabolites were significantly increased in PD patients administered levodopa and were related to the levodopa or entacapone dose but not to disease severity. Levodopa levels were more effectively preserved in PD patients given levodopa/benserazide than in those given levodopa/carbidopa, especially when taken with entacapone. Each dopamine or 3-methoxytyramine level was efficiently expressed with a numerical model using levodopa, entacapone, and selegiline doses as variables, indicative of its application for drug efficacy monitoring. Benserazide (25 mg) blocked AADC and preserved levodopa levels more effectively than carbidopa (10 mg), and entacapone provided a concomitant effect on levodopa level preservation. The drug efficacy of levodopa-associated medication could be monitored by dopamine or 3-methoxytyramine levels.