Protein binding, species differences

Plasma binding - both the quantity and types of proteins in plasma differ in these classes of animals. Mammals tend to have large amounts of protein compared with fish (ca. 8 vs 3 g/100 ml) and albumin, the protein which binds most xenobiotics, is negligible in a number of fish species. 

H. Ericsson, B. Tholander, C. G. Regardh, In vitro Hydrolysis Rate and Protein Binding of Clevidipine, a New Ultrashort-Acting Calcium Antagonist Metabolised by Esterases, in Different Animal Species and Man , Eur. J. Pharm. Sci. 1999, 8, 29-37. 

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. 

Pharmacokinetic (PK) studies in different animal species and additional in vitro studies provide information on the compound s predicted human PK parameters, including dose- and time-dependencies, its protein binding, the effect of food on its PK, and the cytochrome P450 isoenzymes responsible for its metabolism as well as the stmcture and activity of the main metabolites. Also a sensitive assay to quantify the compound and its metabolites in human blood and urine should have been developed and validated. 

Recent evidence confirms that species differences can involve more than one aspect of PPARa-mediated regulation of gene expression. The insensitivity of human liver to rodent peroxisome proliferators is associated with low levels of expression of PPARa in human liver. Marked species differences in the expression of PPARa mRNA have been demonstrated between rodent and human liver, with the latter expressing 1-10% of the levels found in mouse or rat liver (Palmer et al, 1994 Tugwood et al, 1996 Palmer etal, 1998). Using a sensitive and specific immuno/DNA binding assay. Palmer et al (1998) have shown that active PPARa protein is expressed at variable concentrations in human livers. The study compared 20 different human livers and found that those with the highest levels of PPARa protein expression contained less than 10% of the level in mice. Most of the samples (13/20) contained no detectable PPARa activity, but did... 

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. 

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