PURPOSE: To study the PK interaction of L-dopa/benserazide in rats.
METHODS: Male rats received a single oral dose of 80 mg/kg L-dopa or 20 mg/kg 
benserazide or 80/20 mg/kg L-dopa/benserazide. Based on plasma concentrations 
the kinetics of L-dopa, 3-O-methyldopa (3-OMD), benserazide, and its metabolite 
Ro 04-5127 were characterized by noncompartmental analysis and a compartmental 
model where total L-dopa clearance was the sum of the clearances mediated by 
amino-acid-decarboxylase (AADC), catechol-O-methyltransferase and other enzymes. 
In the model Ro 04-5127 inhibited competitively the L-dopa clearance by AADC.
RESULTS: The coadministration of L-dopa/benserazide resulted in a major increase 
in systemic exposure to L-dopa and 3-OMD and a decrease in L-dopa clearance. The 
compartmental model allowed an adequate description of the observed L-dopa and 
3-OMD concentrations in the absence and presence of benserazide. It had an 
advantage over noncompartmental analysis because it could describe the temporal 
change of inhibition and recovery of AADC.
CONCLUSIONS: Our study is the first investigation where the kinetics of 
benserazide and Ro 04-5127 have been described by a compartmental model. The 
L-dopa/benserazide model allowed a mechanism-based view of the 
L-dopa/benserazide interaction and supports the hypothesis that Ro 04-5127 is 
the primary active metabolite of benserazide.