Exposure plasma protein binding

Maximum concentration (Cmax) and exposure (AUQ in toxicity studies at NOAEL using the most sensitive species, based on the concentrations of drug unbound to plasma proteins (for which substantial corrections may be necessary if plasma protein binding in one or more species is above 95%)... 

Data generated from metabolic clearance measurements using liver microsomes can lead to an overestimation of the tme in vivo clearance if the free versus bound fraction is not considered. A useful follow-up assay is therefore plasma protein binding measurement. The impact of cytochrome P-450 inhibition on metabolic clearance of the parent (and thus exposure) is more complicated and it remains rather difficult to make quantitative predictions from in vitro data alone. The reason is that there are generally multiple clearance pathways involved and genetic polymorphism needs to be considered as well. 

Impact of Plasma Protein Binding on PK, Exposure, Safety Margins, Potency Screens and Drug-Drug Interaction... 

Leach, A.G., Jones, H.D., Cosgrove, D.A., Kenny, P.W., Ruston, L., Macfaul, P., Wood, J.M., Colclough, N. and Law, B. (2006) Matched molecular pairs as a guide in the optimization of pharmaceutical properties a study of aqueous solubility, plasma protein binding and oral exposure. Journal of Medicinal Chemistry, 49 (23), 6672-6682. 

This means that overall exposure to unbound drug can t be affected by plasma binding or plasma protein binding displacement interactions. Furthermore, if the drug is a high hepatic extraction-ratio drug, such that CLint >Qj then Q hepatic blood flow rate, becomes limiting, and Equation (12.31) becomes ... 

Aqueous solubility, plasma protein binding, oral exposure AstraZeneca in-house data 1. Phenyl ring additions (i.e Ph-H > Ph-Y) 2. Methylation of heteroatoms (e.g OH>OCHj)... 

During a drug s development it is important to investigate the effect on exposure of changing the dose, and to prove that clearance is dose-independent. When Clp, V2, and tyx remain constant over a dose range and over time, a drug can be said to have linear PK. If an elimination process becomes saturated, AUC tends to increase with dose more than one would expect, if absorption or plasma protein binding are saturated, AUC tends not to increase with dose as much as one would predict. 

Leach AG, Jones HD, Cosgrove DA, et al. Matched molecular pairs as a guide in the optimization of pharmaceutical properties a study of aqueous solubility, plasma protein binding and oral exposure. J Med Chem 2006 49 6672-6682. 

Human exposure to environmental contaminants has been investigated through the analysis of adipose tissue, breast milk, blood and the monitoring of faecal and urinary excretion levels. However, while levels of persistent contaminants in human milk, for example, are extensively monitored, very little is known about foetal exposure to xenobiotics because the concentrations of persistent compounds in blood and trans-placental transmission are less well studied. Also, more information is needed in general about the behaviour of endocrine disruptive compounds (and their metabolites) in vivo, for example the way they bind to blood plasma proteins. 

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