Petrov2018 - C-547 a 6-methyluracil derivative with long-lasting binding and rebinding on acetylcholinesterase
Model Identifier
MODEL1910240001
Short description
C-547, a candidate drug, is a potent slow-binding inhibitor of acetyl-cholinesterase, and the focus of this PK/PD model, which investigates the metabolism and clinical effect of C-547 when it is no longer detectable in the blood. Intended for treatment of myasthenia gravis, this drug and the accompanying model offers a possible treatment for further development of drugs offering neuroprotective effects.
Format
SBML
(L2V4)
Related Publication
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C-547, a 6-methyluracil derivative with long-lasting binding and rebinding on acetylcholinesterase: Pharmacokinetic and pharmacodynamic studies.
- Petrov K, Zueva I, Kovyazina I, Sedov I, Lushchekina S, Kharlamova A, Lenina O, Koshkin S, Shtyrlin Y, Nikolsky E, Masson P
- Neuropharmacology , 3/ 2018 , Volume 131 , pages: 304-315 , PubMed ID: 29277489
- A.E. Arbuzov Institute of Organic and Physical Chemistry of Russian Academy of Sciences, Arbuzov str. 8, Kazan 420088 Russia; Kazan Federal University, Kremlevskaya str, 18, Kazan 420008, Russia.
- C-547, a potent slow-binding inhibitor of acetylcholinesterase (AChE) was intravenously administered to rat (0.05 mg/kg). Pharmacokinetic profiles were determined in blood and different organs: extensor digitorum longus muscle, heart, liver, lungs and kidneys as a function of time. Pharmacokinetics (PK) was studied using non-compartmental and compartmental analyses. A 3-compartment model describes PK in blood. Most of injected C-547 binds to albumin in the bloodstream. The steady-state volume of distribution (3800 ml/kg) is 15 times larger than the distribution volume, indicating a good tissue distribution. C-547 is slowly eliminated (kel = 0.17 h-1; T1/2 = 4 h) from the bloodstream. Effect of C-547 on animal model of myasthenia gravis persists for more than 72 h, even though the drug is not analytically detectable in the blood. A PK/PD model was built to account for such a pharmacodynamical (PD) effect. Long-lasting effect results from micro-PD mechanisms: the slow-binding nature of inhibition, high affinity for AChE and long residence time on target at neuromuscular junction (NMJ). In addition, NMJ spatial constraints i.e. high concentration of AChE in a small volume, and slow diffusion rate of free C-547 out of NMJ, make possible effective rebinding of ligand. Thus, compared to other cholinesterase inhibitors used for palliative treatment of myasthenia gravis, C-547 is the most selective drug, displays a slow pharmacokinetics, and has the longest duration of action. This makes C-547 a promising drug leader for treatment of myasthenia gravis, and a template for development of other drugs against neurological diseases and for neuroprotection.
Contributors
Submitter of the first revision: Johannes Meyer
Submitter of this revision: Johannes Meyer
Modellers: Johannes Meyer
Submitter of this revision: Johannes Meyer
Modellers: Johannes Meyer
Metadata information
Curation status
Non-curated
Modelling approach(es)
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Connected external resources
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| Name | Description | Size | Actions |
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Model files |
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| Petrov2018.xml | SBML L2V4 Representation of Petrov2018 - C-547 a 6-methyluracil derivative with long-lasting binding and rebinding on acetylcholinesterase | 29.01 KB | Preview | Download |
Additional files |
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| Petrov2018.cps | COPASI file of Petrov2018 - C-547 a 6-methyluracil derivative with long-lasting binding and rebinding on acetylcholinesterase | 66.62 KB | Preview | Download |
- Model originally submitted by : Johannes Meyer
- Submitted: Oct 24, 2019 10:52:56 AM
- Last Modified: Oct 24, 2019 10:52:56 AM
Revisions
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Version: 1
- Submitted on: Oct 24, 2019 10:52:56 AM
- Submitted by: Johannes Meyer
- With comment: Import of Petrov2018 - C-547 a 6-methyluracil derivative with long-lasting binding and rebinding on acetylcholinesterase