Plasma protein binding species differences

Walton et al. (2004) determined the extent of interspecies differences in the internal dose of compounds, which are eliminated primarily by renal excretion in humans. Renal excretion was also the main route of elimination in the test species for most of the compounds. Interspecies differences were apparent for both the mechanism of renal excretion (glomemlar filtration, tubular secretion, and/or reabsorption), and the extent of plasma protein binding. Both of these may affect renal clearance and therefore the magnitude of species differences in the internal dose. For compounds which were eliminated unchanged by both humans and the test species, the average difference in the internal dose between humans and animals were 1.6 for dogs, 3.3 for rabbits, 5.2 for rats, and 13 for mice. This suggests that for renal excretion the differences between humans and the rat, and especially the mouse, may exceed the fourfold default factor for toxicokinetics. 

Marked differences in the drug-binding capacity of plasma proteins exist among mammalian species. Variations in the plasma protein binding of drugs may contribute to the species differences in the tissue levels of the drugs, their toxicity, and overall kinetics, particularly if the binding is extensive. 

Son, D. S., M. Osabe, M. Shimoda, and E. Kokue. 1998. Contribution of alpha-l-acid glycoprotein to species difference in lincosamides-plasma protein binding kinetics. Journal of Veterinary Pharmacology and Therapeutics 21 34—40. 

The average fold error (AFE) across this correlation was 1.36. External validation of this approach predicted the human volume of distribution for an additional 9 compounds with an AFE of 1.83. It was recommend that volume of distribution from rat and dog is sufficient to provide a useful prediction of human volume, and that measurement in further species is only warranted if deviations unrelated to plasma protein binding differences are observed in the first two species. Deviations may be caused by active processes which may not scale/translate directly across species. 

Species differences in plasma protein binding are common... 

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