Biomaterial Database

An improved pharmacodynamic model for formation of methemoglobin by antimalarial drugs. 1995

A A Fasanmade, and W J Jusko

Department of Pharmaceutics, School of Pharmacy, State University of New York at Buffalo 14260, USA.

The widely used 8-aminoquinoline antimalarial group of compounds and the derivatives such as WR242511 that are being developed for possible prophylactic anticyanide applications have complex interactions with erythrocytes. Methemoglobin (MetHb) levels following the use of this drug predicted by earlier authors grossly deviated from the observed steady state levels under multiple-dose conditions. We propose a pharmacokinetic-pharmacodynamic model to characterize literature data for blood levels of MetHb generated after administration of WR242511. The model is based on an indirect mechanism involving WR242511 putative metabolite concentration, Cm on the formation of MetHb (rate constant, kr) and on depletion of reducing equivalents leading to accumulation of MetHb. Eventual depletion of MetHb is modeled as related to the disposition of both the drug metabolite and MetHb. The rate of change of MetHb concentration in the blood under the influence of a dose of WR242511 in dogs was governed by this relationship: d[MetHb]/d(t) = kr.Cm.[Hb]-kh.[MetHb], where kr is 2.9 x 10(-5) ml.ng-1.hr-1 and kh is 0.0418 hr-1. This model was validated with multiple-dose data. The model is simple and compatible with the physiological behavior of MetHb in vivo under single-dose and multiple-dose conditions of WR242511 administration.

UI	MeSH Term	Description	Entries
D008432	Mathematical Computing	Computer-assisted interpretation and analysis of various mathematical functions related to a particular problem.	Statistical Computing,Computing, Statistical,Mathematic Computing,Statistical Programs, Computer Based,Computing, Mathematic,Computing, Mathematical,Computings, Mathematic,Computings, Mathematical,Computings, Statistical,Mathematic Computings,Mathematical Computings,Statistical Computings
D008706	Methemoglobin		Ferrihemoglobin
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
D011319	Primaquine	An aminoquinoline that is given by mouth to produce a radical cure and prevent relapse of vivax and ovale malarias following treatment with a blood schizontocide. It has also been used to prevent transmission of falciparum malaria by those returning to areas where there is a potential for re-introduction of malaria. Adverse effects include anemias and GI disturbances. (From Martindale, The Extra Pharmacopeia, 30th ed, p404)	Primacin,Primaquine Diphosphate,Primaquine Phosphate,Diphosphate, Primaquine,Phosphate, Primaquine
D004285	Dogs	The domestic dog, Canis familiaris, comprising about 400 breeds, of the carnivore family CANIDAE. They are worldwide in distribution and live in association with people. (Walker's Mammals of the World, 5th ed, p1065)	Canis familiaris,Dog
D004912	Erythrocytes	Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing HEMOGLOBIN whose function is to transport OXYGEN.	Blood Cells, Red,Blood Corpuscles, Red,Red Blood Cells,Red Blood Corpuscles,Blood Cell, Red,Blood Corpuscle, Red,Erythrocyte,Red Blood Cell,Red Blood Corpuscle
D000042	Absorption	The physical or physiological processes by which substances, tissue, cells, etc. take up or take in other substances or energy.
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia
D000962	Antimalarials	Agents used in the treatment of malaria. They are usually classified on the basis of their action against plasmodia at different stages in their life cycle in the human. (From AMA, Drug Evaluations Annual, 1992, p1585)	Anti-Malarial,Antimalarial,Antimalarial Agent,Antimalarial Drug,Anti-Malarials,Antimalarial Agents,Antimalarial Drugs,Agent, Antimalarial,Agents, Antimalarial,Anti Malarial,Anti Malarials,Drug, Antimalarial,Drugs, Antimalarial
D015203	Reproducibility of Results	The statistical reproducibility of measurements (often in a clinical context), including the testing of instrumentation or techniques to obtain reproducible results. The concept includes reproducibility of physiological measurements, which may be used to develop rules to assess probability or prognosis, or response to a stimulus; reproducibility of occurrence of a condition; and reproducibility of experimental results.	Reliability and Validity,Reliability of Result,Reproducibility Of Result,Reproducibility of Finding,Validity of Result,Validity of Results,Face Validity,Reliability (Epidemiology),Reliability of Results,Reproducibility of Findings,Test-Retest Reliability,Validity (Epidemiology),Finding Reproducibilities,Finding Reproducibility,Of Result, Reproducibility,Of Results, Reproducibility,Reliabilities, Test-Retest,Reliability, Test-Retest,Result Reliabilities,Result Reliability,Result Validities,Result Validity,Result, Reproducibility Of,Results, Reproducibility Of,Test Retest Reliability,Validity and Reliability,Validity, Face