Protein-binding factors affecting

The half lives of hormones differ with some having very short half lives of less than a few minutes e.g. ACTH, epinephrine and nor-epinephrine, with other hormones e.g., erythropoietin having half lives of about 2-3 h in the mouse and 8-lOh in the dog. (see Woodman,1997 and Reimers,1999 for detailed descriptions of animal hormone structures and properties). The binding of circulating T3 and T4 to plasma proteins differs, and for the hormones that are bound to plasma proteins, any factors affecting protein synthesis and the ratio of freedotal hormone levels must be considered when interpreting data. 

Figure 26-5. Factors affecting cholesterol balance at the cellular level. Reverse cholesterol transport may be initiated by pre 3 HDL binding to the ABC-1 transporter protein via apo A-l. Cholesterol is then moved out of the cell via the transporter, lipidating the HDL, and the larger particles then dissociate from the ABC-1 molecule. (C, cholesterol CE, cholesteryl ester PL, phospholipid ACAT, acyl-CoA cholesterol acyltransferase LCAT, lecithinicholesterol acyltransferase A-l, apolipoprotein A-l LDL, low-density lipoprotein VLDL, very low density lipoprotein.) LDL and HDL are not shown to scale.

The presence of serum-binding proteins. Some biopharmaceuticals (including insulin-like growth factor (IGF), GH and certain cytokines) are notable in that the blood contains proteins that specifically bind them. Such binding proteins can function naturally as transporters or activators, and binding can affect characteristics such as serum elimination rates. 

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. 

Water binding varies with the number and type of polar groups (5 ). Other factors that affect the mechanism of protein-water interactions include protein conformation and environmental factors that affect protein polarity and/or conformation. Conformational changes in the protein molecules can affect the nature and availability of the hydration sites. Transition from globular to random coil conformation may expose previously buried amino acid side chains, thereby making them available to interact with aqueous medium. Consequently, an unfolded conformation may permit the protein to bind more water than was possible in the globular form ( ). 

It is important to note that the elimination half-life is a derived term, and any process that changes k will change the half-life of the drug. Factors that may affect pharmacokinetic parameters are discussed elsewhere, but in this example may include disease states, changes in urinary pH, changes in plasma protein binding, and coadministration of other drugs. 

---