A pharmacokinetic model to predict the PK interaction of L-dopa and benserazide in rats
Geoffrey
Nunns
Bioengineering Institute, University of Auckland
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
model diagram
Schematic diagram of the conceptual model to describe kinetics of L-dopa and 3-OMD.
A pharmacokinetic model to predict the PK interaction of L-dopa and benserazide in rats (L-dopa)
Nunns
Geoffrey
Rogan
gnunns1@jhu.edu
The University of Auckland
Auckland Bioengineering Institute
2009-10-19
The Grange et al. 2001 pharmokinetic model of the PK interaction of L-Dopa and Benserazide in Rats
This is the CellML description of the Grange et al.'s pharmokinetic model of the PK interaction of L-Dopa and Benserazide in Rats
Geoffrey Nunns
Rat
keyword
metabolism
PKPD
L-dopa
11587490
Grange
Susan
Holford
Nicholas
H
G
Guentert
Theodor
W
A pharmacokinetic model to predict the PK interaction of L-dopa and benserazide in rats
2001-05-4
Pharm Res.
18
1174
1184