Grange, Holford, Guentert, 2001

Model Status

This CellML model runs in PCenv, COR and OpenCell to recreate the published results (Figure 6). This model is simulates the administration of L-dopa only, without benserazide added. This model was created using the paper equations supplemented by suggestions made by Dr. Holford, as the original code was not available.

Model Structure

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.

The original paper reference is cited below:

A pharmacokinetic model to predict the PK interaction of L-dopa and benserazide in rats, Susan Grange, Nicholas H. G. Holford, Theodor W. Guentert, 2001, Pharm Res., volume 18, 1174-1184. PubMed ID: 11587490

Schematic diagram of the conceptual model to describe kinetics of L-dopa and 3-OMD.