Biomaterial Database

The effect of malignant effusions on methotrexate disposition. 2002

Jing Li, and Peter Gwilt

Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, 986025 Nebraska Medical Center, Omaha 68198-6025, USA.

OBJECTIVE The purpose of this study was to evaluate the effect of malignant effusions on the pharmacokinetics of methotrexate (MTX). METHODS Simulated drug concentrations in blood, tissues and effusion fluid spaces were generated using a previously published physiologically based pharmacokinetic (PBPK) model for MTX in humans. The model was expanded to incorporate effusion spaces with permeability rate-limited drug transport. The model was used first to simulate MTX plasma concentrations in patients without effusions. Then the effects of cardiac, peritoneal and pleural effusions on MTX plasma concentrations were investigated followed by an examination of the influence of effusion volume, binding in the effusate, and effusion space permeability clearance (PA) on MTX plasma pharmacokinetics. In addition, the effect of the disposition characteristics (e.g. volume of distribution) of the anticancer drug on the overall influence of an effusate was evaluated. Finally, the simulations were compared with MTX concentrations observed in the plasma and pleural fluid of a patient with a pleural effusion treated with MTX. RESULTS There was good agreement between the PBPK-simulated MTX plasma concentrations and observed values in patients without effusions. There was also a remarkable similarity between simulated and measured plasma and effusion MTX concentrations in a pediatric patient with a malignant pleural effusion. The physiological characteristics of an effusion, i.e. fluid volume, protein binding and membrane permeability clearance, modulate the influence of an effusion on the drug plasma concentration-time course. In general, effusions cause an increase in the steady-state volume of distribution but no change in the overall clearance of a drug. Malignant effusions were noticeable only in the disposition phase of MTX resulting in an apparent "third space." This was most prominent when the effusion fluid volume was large, the binding of MTX in the effusion fluid was greater than in plasma and the PA value was low. The percentage change in terminal half-life due to an effusion is significant for drugs with small volumes of distribution (332%) but not for those with large volumes of distribution (1.29%). In the case of MTX, and probably other anticancer drugs, the resulting increase in half-life may be associated with unanticipated toxicity.

UI	MeSH Term	Description	Entries
D008727	Methotrexate	An antineoplastic antimetabolite with immunosuppressant properties. It is an inhibitor of TETRAHYDROFOLATE DEHYDROGENASE and prevents the formation of tetrahydrofolate, necessary for synthesis of thymidylate, an essential component of DNA.	Amethopterin,Methotrexate Hydrate,Methotrexate Sodium,Methotrexate, (D)-Isomer,Methotrexate, (DL)-Isomer,Methotrexate, Dicesium Salt,Methotrexate, Disodium Salt,Methotrexate, Sodium Salt,Mexate,Dicesium Salt Methotrexate,Hydrate, Methotrexate,Sodium, Methotrexate
D008954	Models, Biological	Theoretical representations that simulate the behavior or activity of biological processes or diseases. For disease models in living animals, DISEASE MODELS, ANIMAL is available. Biological models include the use of mathematical equations, computers, and other electronic equipment.	Biological Model,Biological Models,Model, Biological,Models, Biologic,Biologic Model,Biologic Models,Model, Biologic
D010490	Pericardial Effusion	Fluid accumulation within the PERICARDIUM. Serous effusions are associated with pericardial diseases. Hemopericardium is associated with trauma. Lipid-containing effusion (chylopericardium) results from leakage of THORACIC DUCT. Severe cases can lead to CARDIAC TAMPONADE.	Chylopericardium,Hemopericardium,Chylopericardiums,Effusion, Pericardial,Effusions, Pericardial,Pericardial Effusions
D010539	Permeability	Property of membranes and other structures to permit passage of light, heat, gases, liquids, metabolites, and mineral ions.	Permeabilities
D003198	Computer Simulation	Computer-based representation of physical systems and phenomena such as chemical processes.	Computational Modeling,Computational Modelling,Computer Models,In silico Modeling,In silico Models,In silico Simulation,Models, Computer,Computerized Models,Computer Model,Computer Simulations,Computerized Model,In silico Model,Model, Computer,Model, Computerized,Model, In silico,Modeling, Computational,Modeling, In silico,Modelling, Computational,Simulation, Computer,Simulation, In silico,Simulations, Computer
D006207	Half-Life	The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity.	Halflife,Half Life,Half-Lifes,Halflifes
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000964	Antimetabolites, Antineoplastic	Antimetabolites that are useful in cancer chemotherapy.	Antineoplastic Antimetabolites
D001202	Ascitic Fluid	The serous fluid of ASCITES, the accumulation of fluids in the PERITONEAL CAVITY.	Peritoneal Effusion,Peritoneal Fluid,Ascitic Fluids,Effusion, Peritoneal,Fluid, Ascitic,Fluid, Peritoneal,Peritoneal Effusions,Peritoneal Fluids
D012212	Rheology	The study of the deformation and flow of matter, usually liquids or fluids, and of the plastic flow of solids. The concept covers consistency, dilatancy, liquefaction, resistance to flow, shearing, thixotrophy, and VISCOSITY.	Flowmetry,Velocimetry,Velocimetries