Dataset Information

Grange2001 - L Dopa PK model

ABSTRACT: Grange2001 - L-dopa PK model A pharmacokinetics of L-dopa in rats after administration of L-dopa alone (this model: BIOMD0000000321) or L-dopa combined with a peripheral AADC (amino-acid-decarboxylase) inhibitor (BIOMD0000000320) has been studied using noncompartmental analysis. This model is described in the article: A pharmacokinetic model to predict the PK interaction of L-dopa and benserazide in rats. Grange S, Holford NH, Guentert TW Pharmaceutical Research [2001, 18(8):1174-1184] Abstract: 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 model has a species (A-dopa) whose initial concentration is calculated from a listOfInitialAssignments . While running for the first time the time-course (24hrs) for this model in COPASI (up to version 4.6, Build 33), the resulting graph displays only straight lines for all the species. Any subsequent runs should provide proper plots (i.e. without making any change to the model, just by clicking the "run" button again). The above issue is caused by some initial assignments which are not calculated when COPASI imports the file. This issue should not be present in newer releases of COPASI. This model is hosted on BioModels Database and identified by: MODEL1103250000 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

DISEASE(S): Parkinson's Disease

SUBMITTER: Lukas Endler

PROVIDER: BIOMD0000000321 | BioModels | 2024-09-02

REPOSITORIES: BioModels

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			Action	DRS
	BIOMD0000000321?filename=BIOMD0000000321-biopax2.owl	Owl
	BIOMD0000000321?filename=BIOMD0000000321-biopax3.owl	Owl
	BIOMD0000000321?filename=BIOMD0000000321.m	Other
	BIOMD0000000321?filename=BIOMD0000000321.pdf	Pdf
	BIOMD0000000321?filename=BIOMD0000000321.png	Other

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

Grange S S Holford N H NH Guentert T W TW

Pharmaceutical research 20010801 8

<h4>Purpose</h4>To study the PK interaction of L-dopa/benserazide in rats.<h4>Methods</h4>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 (A ...[more]

PMID: 11587490

Similar Datasets

Project description:Grange2001 - PK interaction of L-dopa and benserazide A pharmacokinetics of L-dopa in rats after administration of L-dopa alone (BIOMD0000000321) or L-dopa combined with a peripheral AADC (amino-acid-decarboxylase) inhibitor (this model: BIOMD0000000320) has been studied using noncompartmental analysis. This model is described in the article: A pharmacokinetic model to predict the PK interaction of L-dopa and benserazide in rats. Grange S, Holford NH, Guentert TW Pharmaceutical Research [2001, 18(8):1174-1184] Abstract: 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 volumes and variables in this model are taken for a rat with 0.25 kg. The inital dose for L_Dopa (L_Dopa_per_kg_rat) and Benserazide (Benserazide_per_kg_rat) are to be given in umole per kg. 80 mg/kg L-Dopa correspond to 404 umol/kg, 20 mg/kg benserazide to 78 umol/kg. To change the model to a different mass of rat the compartment volumes, and the parameters rat_body_mass and Q have to changed accordingly. The model has three species (A-dopa, A_B, A_M) whose initial concentrations are calculated from a listOfInitialAssignments . While running for the first time the time-course (24hrs) for this model in COPASI (up to version 4.6, Build 33), the resulting graph displays only straight lines for all the species. Any subsequent runs should provide proper plots (i.e. without making any change to the model, just by clicking the "run" button again). The above issue is caused by some initial assignments which are not calculated when COPASI imports the file. This issue should not be present in newer releases of COPASI. This model is hosted on BioModels Database and identified by: MODEL0910130001 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Project description:The anti-epileptic drug zonisamide is reported to exert beneficial effects in patients with Parkinson's disease. To elucidate the pathophysiological mechanisms underlying the anti-parkinsonism effects of zonisamide, we examined the effect of zonisamide co-administered with levodopa in the striata of rats with 6-hydoroxydopamine hemiparkinsonism by using a DNA microarray for genome-wide gene expression profiling. We found that the expression of some genes related to metabolism and nervous system development and function were upregulated by zonisamide; expression of these genes was downregulated by levodopa. Furthermore, many genes related to the immune system and inflammation were downregulated by zonisamide, and their expression was upregulated by levodopa. These results indicate that zonisamide has a protective effect when co-administered with levodopa. Rats were anesthetized with pentobarbital 240 mg/kg, i.p. and unilateral lesions of the left medial forebrain bundle were made via injection of 8 mg 6-OHDA hydrobromide in 4 ml of sterile saline containing 0.01% ascorbic acid. Motor disturbance was assessed by counting the number of full rotations per min in a cylindrical container of M-OM-^F30 cm diameter at 10-min intervals for the first 60 min after METH (3 mg/kg, i.p.) administration [3]. Behavioral screening was carried out after 2-3 weeks of recovery and animals that performed at least 7 turns/min during METH challenge were certified as hemiparkinsonism rats and included in the study. Seven days after METH challenge, hemiparkinsonism rats were treated with saline, L-DOPA (100 mg/kg, i.p.), or L-DOPA (100 mg/kg, i.p.) and ZNS (50 mg/kg, i.p.) once per day for 7 days. L-DOPA was injected 30 min after benserazide hydrochloride (a peripheral decarboxylase inhibitor). ZNS was injected 30 min after L-DOPA injection. The 4 experimental groups were classified as follows: the non-lesioned side of saline-treated 6-OHDA-injected rats (NL), the lesioned side of saline-treated 6-OHDA-injected rats (SL), the lesioned side of L-DOPA-treated 6-OHDA-injected rats (DL), and the lesioned side of L-DOPA and ZNS-treated 6-OHDA-injected rats (ZDL). Three animals were assigned to each group.