Brain penetration of benserazide inversely associates with levodopa response in Parkinson’s disease

Levodopa combined with a peripheral DOPA decarboxylase inhibitor (DDCI) is the first-line treatment for Parkinson’s disease (PD), yet interindividual response variability remains poorly understood. Whether DDCIs penetrate the central nervous system (CNS) in the context of potential blood–brain barrier (BBB) dysfunction in PD and influence levodopa efficacy is unclear. We therefore assessed CNS exposure of benserazide (BZ) and its active metabolite 2,3,4-trihydroxybenzylhydrazine (THBH) and their association with levodopa response. Fifteen PD patients (Hoehn-Yahr 2–3) underwent a standardized levodopa challenge test and were classified as good (≥50% improvement) or poor responders. Paired blood and cerebrospinal fluid (CSF) samples were collected after a single oral dose of levodopa/BZ (200/50 mg), and analyte concentrations were quantified using ultra-high-performance liquid chromatography with electrochemical detection (UPLC-ECD). Both BZ and THBH were detectable in CSF, indicating BBB penetration. CSF concentrations and CSF-to-plasma ratios of total BZ (BZ + THBH) were significantly higher in poor responders ( p = 0.021 and 0.014, respectively) and negatively correlated with levodopa efficacy ( p = 0.034 and 0.008, respectively). In contrast, levodopa concentrations and Q Alb did not differ between groups. These findings demonstrate CNS exposure of BZ/THBH and suggest that increased central DDCI exposure may contribute to reduced levodopa responsiveness.