FORMATION AND PROTEIN BINDING OF THE ACYL GLUCURONIDE OF A LEUKOTRIENE B4 ANTAGONIST (SB-209247): RELATION TO SPECIES DIFFERENCES IN HEPATOTOXICITY

The dog is a commonly used animal model by virtue of its size, well-characterized physiology, and ease of handling. For these reasons and others, dogs are also useful in pharmacokinetic and metabolism studies during the development of both human and veterinary pharmaceutical products. In comparison with humans, or with other animals, dogs have some unique physiologic attributes that can affect the disposition of drugs. Species differences in gastrointestinal physiology, metabolism, renal function, and protein binding can affect the correlation of the pharmacokinetics and toxicology of dogs with those of other species. With the use of relevant examples, this article will provide an introduction to characteristics of dog physiology and their impact on pharmacokinetics, metabolism, drug disposition, toxicity, and dose selection.

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Species differences in drug plasma protein binding

MedChemComm ◽

10.1039/c4md00148f ◽

2014 ◽

Vol 5 (7) ◽

pp. 963-967 ◽

Cited By ~ 27

Author(s):

Nicola Colclough ◽

Linette Ruston ◽

J. Matthew Wood ◽

Philip A. MacFaul

Keyword(s):

Drug Discovery ◽

Protein Binding ◽

Human Plasma ◽

Plasma Protein Binding ◽

Plasma Protein ◽

Plasma Proteins ◽

Species Differences ◽

Human Plasma Protein ◽

Binding Data ◽

Drug Plasma

Comparison of the human plasma protein binding data for a variety of drug discovery compounds indicates that compounds tend to be slightly more bound to human plasma proteins, than compared to plasma proteins from rats, dogs or mice.

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Diclofenac Covalent Protein Binding Is Dependent on Acyl Glucuronide Formation and Is Inversely Related to P450-Mediated Acute Cell Injury in Cultured Rat Hepatocytes

Toxicology and Applied Pharmacology ◽

10.1006/taap.1993.1097 ◽

1993 ◽

Vol 120 (1) ◽

pp. 155-161 ◽

Cited By ~ 120

Author(s):

A. Kretzrommel ◽

U.A. Boelsterli

Keyword(s):

Protein Binding ◽

Cell Injury ◽

Rat Hepatocytes ◽

Acyl Glucuronide ◽

Cultured Rat Hepatocytes ◽

Covalent Protein Binding

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Protein binding and pharmacokinetics of reactive acyl glucuronide drug metabolites

Toxicology ◽

10.1016/j.tox.2010.08.108 ◽

2010 ◽

Vol 278 (3) ◽

pp. 357-358

Author(s):

Thomas G. Hammond ◽

Sophie L. Regan ◽

Xiaoli Meng ◽

James L. Maggs ◽

Rosalind E. Jenkins ◽

...

Keyword(s):

Protein Binding ◽

Drug Metabolites ◽

Acyl Glucuronide

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Cross-Species Differential Plasma Protein Binding of MBX-102/JNJ39659100: A Novel PPAR- Agonist

PPAR Research ◽

10.1155/2008/465715 ◽

2008 ◽

Vol 2008 ◽

pp. 1-10 ◽

Cited By ~ 8

Author(s):

Holly J. Clarke ◽

Francine Gregoire ◽

Fang Ma ◽

Robert Martin ◽

Spring Zhao ◽

...

Keyword(s):

Protein Binding ◽

Plasma Protein Binding ◽

Plasma Protein ◽

Species Differences ◽

Free Drug ◽

Drug Binding ◽

Mouse Serum ◽

Drug Levels ◽

Ppar Agonist ◽

Interspecies Differences

Drug binding to plasma proteins restricts their free and active concentrations, thereby affecting their pharmacokinetic properties. Species differences in plasma protein levels complicate the understanding of interspecies pharmacodynamic and toxicological effects. MBX-102 acid/JNJ39659100 is a novel PPAR- agonist in development for the treatment of type 2 diabetes. Studies were performed to evaluate plasma protein binding to MBX-102 acid and evaluate species differences in free drug levels. Equilibrium dialysis studies demonstrated that MBX-102 acid is highly bound (>98%) to human, rat and mouse albumin and that free MBX-102 acid levels are higher in rodent than in human plasma. Interspecies differences in free drug levels were further studied using PPAR- transactivation assays and a newly developed PPAR- corepressor displacement (biochemical) assay. PPAR- transactivation and corepressor displacement by MBX-102 acid was higher in rat and mouse serum than human serum. These results confirm the relevance of interspecies differences in free MBX-102 acid levels.

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Scanning Electron Microscopy of Fish Scales as an Adjunctive Aid in Speciation

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100095236 ◽

1972 ◽

Vol 30 ◽

pp. 394-395

Author(s):

Edward D. DeLamater ◽

Walter R. Courtenay ◽

Cecil Whitaker

Keyword(s):

Electron Microscopy ◽

Scanning Electron Microscopy ◽

Lateral Line ◽

Species Differences ◽

Fish Scale ◽

Fish Scales ◽

Anterior Border ◽

The University ◽

Multiple Holes ◽

Scanning Electron

Comparative scanning electron microscopy studies of fish scales of different orders, families, genera and species within genera have demonstrated differences which warrant elaboration. These differences in detail appear to be sufficient to act as “fingerprints”, at least, for family differences. To date, the lateral line scales have been primarily studied. These demonstrate differences in the lateral line canals; the pattern of ridging with or without secondary protuberances along the edges; the pattern of spines or their absence on the anterior border of the scales; the presence or absence of single or multiple holes on the ventral and dorsal sides of the lateral line canal covers. The distances between the ridges in the pattern appear likewise to be important.A statement of fish scale structure and a comparison of family and species differences will be presented.The authors wish to thank Dr. Donald Marzalek and Mr. Wallace Charm of the Marine and Atmospheric Laboratory of the University of Miami and Dr. Sheldon Moll and Dr. Richard Turnage of AMR for their exhaustive help in these preliminary studies.

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