A pharmacokinetic model to predict the PK interaction of l-dopa and benserazide in rats

Purpose. To study the PK interaction of L-dopa/benserazide in rats. Methods. Mate 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 concentra tions 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 cleara nces mediated by amino-acid-decarboxylase (AADC), catechol-O-methyltransfer ase 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 inc rease in systemic exposure to L-dopa and 3-OMD and a decrease in L-dopa cle arance. The compartmental model allowed an adequate description of the obse rved L-dopa and 3-OMD concentrations in the absence and presence of bensera zide. It had an advantage over noncompartmental analysis because it could d escribe the temporal change of inhibition and recovery of AADC. Conclusions. Our study is the first investigation where the kinetics of ben serazide and Ro 04-5127 have been described by a compartmental model. The L -dopalhenserazide model allowed a mechanism-based view of the L-dopa/benser azide interaction and supports the hypothesis that Ro 04-5127 is the primar y active metabolite of benserazide.