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Evaluation of blood-brain barrier transport and CNS drug metabolism in diseased and control brain after intravenous L-DOPA in a unilateral rat model of Parkinson's disease.

Ravenstijn PG, Drenth HJ, O'Neill MJ, Danhof M, de Lange EC - Fluids Barriers CNS (2012)

Bottom Line: In rotenone responders (71%), no difference in L-DOPA BBB transport was found between diseased and control cerebral hemisphere.Parkinson's disease-like pathology, indicated by a huge reduction of tyrosine hydroxylase as well as by substantially reduced levels and higher elimination rates of DOPAC and HVA, does not result in changes in BBB transport of L-DOPA.Taking the results of this study and that of previous ones, it can be concluded that changes in BBB functionality are not a specific characteristic of Parkinson's disease, and cannot account for the decreased benefit of L-DOPA at later stages of Parkinson's disease.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Pharmacology, LACDR Leiden University, Leiden, The Netherlands. l.lange@lacdr.leidenuniv.nl.

ABSTRACT

Background: Changes in blood-brain barrier (BBB) functionality have been implicated in Parkinson's disease. This study aimed to investigate BBB transport of L-DOPA transport in conjunction with its intra-brain conversion, in both control and diseased cerebral hemispheres in the unilateral rat rotenone model of Parkinson's disease.

Methods: In Lewis rats, at 14 days after unilateral infusion of rotenone into the medial forebrain bundle, L-DOPA was administered intravenously (10, 25 or 50 mg/kg). Serial blood samples and brain striatal microdialysates were analysed for L-DOPA, and the dopamine metabolites DOPAC and HVA. Ex-vivo brain tissue was analyzed for changes in tyrosine hydroxylase staining as a biomarker for Parkinson's disease severity. Data were analysed by population pharmacokinetic analysis (NONMEM) to compare BBB transport of L-DOPA in conjunction with the conversion of L-DOPA into DOPAC and HVA, in control and diseased cerebral hemisphere.

Results: Plasma pharmacokinetics of L-DOPA could be described by a 3-compartmental model. In rotenone responders (71%), no difference in L-DOPA BBB transport was found between diseased and control cerebral hemisphere. However, in the diseased compared with the control side, basal microdialysate levels of DOPAC and HVA were substantially lower, whereas following L-DOPA administration their elimination rates were higher.

Conclusions: Parkinson's disease-like pathology, indicated by a huge reduction of tyrosine hydroxylase as well as by substantially reduced levels and higher elimination rates of DOPAC and HVA, does not result in changes in BBB transport of L-DOPA. Taking the results of this study and that of previous ones, it can be concluded that changes in BBB functionality are not a specific characteristic of Parkinson's disease, and cannot account for the decreased benefit of L-DOPA at later stages of Parkinson's disease.

No MeSH data available.


Related in: MedlinePlus

The population pharmacokinetic model for L-DOPA, DOPAC and HVA comprising of three compartments (1-3) describing the pharmacokinetics of L-DOPA in plasma, two compartments (4 and 5) describing the pharmacokinetics of L-DOPA in brainECF, one for the control cerebral hemisphere and one for the rotenone-treated responder cerebral hemisphere, two compartments (6 and 8) describing the kinetics of DOPAC in brainECF, one for the control cerebral hemisphere and one for the rotenone-treated responder cerebral hemisphere and two compartments (7 and 9) describing the kinetics of HVA in brainECF, one for the control cerebral hemisphere and one for the rotenone-treated responder cerebral hemisphere. (V = volume of distribution, Q = inter-compartmental clearance, k = elimination rate constant, Kin = endogenous formation rate constant of L-DOPA.).
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Figure 1: The population pharmacokinetic model for L-DOPA, DOPAC and HVA comprising of three compartments (1-3) describing the pharmacokinetics of L-DOPA in plasma, two compartments (4 and 5) describing the pharmacokinetics of L-DOPA in brainECF, one for the control cerebral hemisphere and one for the rotenone-treated responder cerebral hemisphere, two compartments (6 and 8) describing the kinetics of DOPAC in brainECF, one for the control cerebral hemisphere and one for the rotenone-treated responder cerebral hemisphere and two compartments (7 and 9) describing the kinetics of HVA in brainECF, one for the control cerebral hemisphere and one for the rotenone-treated responder cerebral hemisphere. (V = volume of distribution, Q = inter-compartmental clearance, k = elimination rate constant, Kin = endogenous formation rate constant of L-DOPA.).

Mentions: On the basis of selection criteria, the plasma and brainECF L-DOPA data from the individual rats were simultaneously analysed (Figure 1; compartments 1-5). First, clearances from compartment 1 to 4 (Cl14), compartment 4 to 1 (Cl41), compartment 1 to 5 (Cl15) and compartment 5 to 1 (Cl51) were assigned in the structural model to seek for concentration-dependent BBB transport of L-DOPA via the LAT-1 transporter. However, although a large range of plasma concentration data was available (3 dosages of L-DOPA), no asymmetry in BBB transport could be identified. The model was therefore simplified to use the inter-compartmental clearances Q4 and Q5.


Evaluation of blood-brain barrier transport and CNS drug metabolism in diseased and control brain after intravenous L-DOPA in a unilateral rat model of Parkinson's disease.

Ravenstijn PG, Drenth HJ, O'Neill MJ, Danhof M, de Lange EC - Fluids Barriers CNS (2012)

The population pharmacokinetic model for L-DOPA, DOPAC and HVA comprising of three compartments (1-3) describing the pharmacokinetics of L-DOPA in plasma, two compartments (4 and 5) describing the pharmacokinetics of L-DOPA in brainECF, one for the control cerebral hemisphere and one for the rotenone-treated responder cerebral hemisphere, two compartments (6 and 8) describing the kinetics of DOPAC in brainECF, one for the control cerebral hemisphere and one for the rotenone-treated responder cerebral hemisphere and two compartments (7 and 9) describing the kinetics of HVA in brainECF, one for the control cerebral hemisphere and one for the rotenone-treated responder cerebral hemisphere. (V = volume of distribution, Q = inter-compartmental clearance, k = elimination rate constant, Kin = endogenous formation rate constant of L-DOPA.).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3298802&req=5

Figure 1: The population pharmacokinetic model for L-DOPA, DOPAC and HVA comprising of three compartments (1-3) describing the pharmacokinetics of L-DOPA in plasma, two compartments (4 and 5) describing the pharmacokinetics of L-DOPA in brainECF, one for the control cerebral hemisphere and one for the rotenone-treated responder cerebral hemisphere, two compartments (6 and 8) describing the kinetics of DOPAC in brainECF, one for the control cerebral hemisphere and one for the rotenone-treated responder cerebral hemisphere and two compartments (7 and 9) describing the kinetics of HVA in brainECF, one for the control cerebral hemisphere and one for the rotenone-treated responder cerebral hemisphere. (V = volume of distribution, Q = inter-compartmental clearance, k = elimination rate constant, Kin = endogenous formation rate constant of L-DOPA.).
Mentions: On the basis of selection criteria, the plasma and brainECF L-DOPA data from the individual rats were simultaneously analysed (Figure 1; compartments 1-5). First, clearances from compartment 1 to 4 (Cl14), compartment 4 to 1 (Cl41), compartment 1 to 5 (Cl15) and compartment 5 to 1 (Cl51) were assigned in the structural model to seek for concentration-dependent BBB transport of L-DOPA via the LAT-1 transporter. However, although a large range of plasma concentration data was available (3 dosages of L-DOPA), no asymmetry in BBB transport could be identified. The model was therefore simplified to use the inter-compartmental clearances Q4 and Q5.

Bottom Line: In rotenone responders (71%), no difference in L-DOPA BBB transport was found between diseased and control cerebral hemisphere.Parkinson's disease-like pathology, indicated by a huge reduction of tyrosine hydroxylase as well as by substantially reduced levels and higher elimination rates of DOPAC and HVA, does not result in changes in BBB transport of L-DOPA.Taking the results of this study and that of previous ones, it can be concluded that changes in BBB functionality are not a specific characteristic of Parkinson's disease, and cannot account for the decreased benefit of L-DOPA at later stages of Parkinson's disease.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Pharmacology, LACDR Leiden University, Leiden, The Netherlands. l.lange@lacdr.leidenuniv.nl.

ABSTRACT

Background: Changes in blood-brain barrier (BBB) functionality have been implicated in Parkinson's disease. This study aimed to investigate BBB transport of L-DOPA transport in conjunction with its intra-brain conversion, in both control and diseased cerebral hemispheres in the unilateral rat rotenone model of Parkinson's disease.

Methods: In Lewis rats, at 14 days after unilateral infusion of rotenone into the medial forebrain bundle, L-DOPA was administered intravenously (10, 25 or 50 mg/kg). Serial blood samples and brain striatal microdialysates were analysed for L-DOPA, and the dopamine metabolites DOPAC and HVA. Ex-vivo brain tissue was analyzed for changes in tyrosine hydroxylase staining as a biomarker for Parkinson's disease severity. Data were analysed by population pharmacokinetic analysis (NONMEM) to compare BBB transport of L-DOPA in conjunction with the conversion of L-DOPA into DOPAC and HVA, in control and diseased cerebral hemisphere.

Results: Plasma pharmacokinetics of L-DOPA could be described by a 3-compartmental model. In rotenone responders (71%), no difference in L-DOPA BBB transport was found between diseased and control cerebral hemisphere. However, in the diseased compared with the control side, basal microdialysate levels of DOPAC and HVA were substantially lower, whereas following L-DOPA administration their elimination rates were higher.

Conclusions: Parkinson's disease-like pathology, indicated by a huge reduction of tyrosine hydroxylase as well as by substantially reduced levels and higher elimination rates of DOPAC and HVA, does not result in changes in BBB transport of L-DOPA. Taking the results of this study and that of previous ones, it can be concluded that changes in BBB functionality are not a specific characteristic of Parkinson's disease, and cannot account for the decreased benefit of L-DOPA at later stages of Parkinson's disease.

No MeSH data available.


Related in: MedlinePlus