Question 7

Describe protein binding and its significance in pharmacology.

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College Answer

Descriptions of protein binding were generally too brief (e.g. a statement saying that drugs and hormones bind to proteins in the plasma rather than a description of usually reversible binding with a drug-protein equilibrium).

It was expected that the factors which determine protein binding would be described. Marks were attributed if proteins, along with characteristics of the drugs they bind, were named. Candidates achieved better marks if they named the pharmacological parameters affected by protein binding and explained how and why change occurs along with the significance of those changes. Few candidates differentiated between tissue and plasma protein binding and the different effects on the volume of distribution.

Discussion

  • Protein binding of drugs is the formation of reversible complexes between drugs and blood components, which may include plasma proteins and the constituents of red cells
  • The main determinants of protein binding are:
    • Number of available binding sites (i.e. protein concentration)
    • Number of drug molecules (i.e. drug concentration)
    • Association constant of the drug and binding site (K)
    • Lipophilicity and pKa of the drug (lipid-soluble drugs tend to be more protein-bound)
    • Resemblance to endogenous ligands of the transport protein
  • Environmental conditions which influence protein binding:
    • pH (affects drug lipid solubility and K value)
    • Endogenous ligands  for the same binding sites, eg bilirubin
    • Protein level obviously affects the protein binding because the number of total available binding sites is affected.
    • Temperature should be mentioned, but let's face it, under the vast majority of circumstances the relevant temperature is going to be normal body temperature or 1-2 degrees above or below.
  • Proteins and blood components that bind drugs:
    • ​​​​​​Albumin (most drugs; six binding sites)
    • α-1 acid glycoprotein ("basic" drugs and steroid molecules) 
    • Lipoproteins (lipid-soluble drugs, eg. cannabinoids and cyclosporin)
    • Globulins (eg. ceruloplasmin binds vitamins A,D, E and K)
    • Haemoglobin (pentobarbital, phenytoin and phenothiazines)
    • RBC membrane (chlorpromazine and imipramine).
    • Carbonic anhydrase "(acetazolamide, chlorthalidone)
    • Specific transport proteins, eg. thyroxin-binding globulin  
  • Clinical significance of drug protein binding:
    • VOD: smaller for drugs with are highly plasma protein bound, larger for drugs which are highly tissue protein-bound
    • Metabolism and clearance: only the free fraction is usually available for dialysis, renal elimination and hepatic metabolism (with some exceptions)
    • Measured drug levels: total drug level may underrepresent clinically relevant concentration of free biologically active drug if there is hypoalbuminaemia
    • Displacement by other drugs, where there is competition for binding sites.

References

Olson, Richard E., and David D. Christ. "Plasma protein binding of drugs." Annual reports in medicinal chemistry 31 (1996): 327-336.

Yang, Feng, Yao Zhang, and Hong Liang. "Interactive association of drugs binding to human serum albumin." International journal of molecular sciences 15.3 (2014): 3580-3595.

Gillette, James R. "Overview of drug‐protein binding." Annals of the New York Academy of Sciences 226.1 (1973): 6-17.

Koch-Weser, Jan, and Edward M. Sellers. "Binding of drugs to serum albumin." New England Journal of Medicine 294.6 (1976): 311-316.

Sudlow, G. D. J. B., D. J. Birkett, and D. N. Wade. "The characterization of two specific drug binding sites on human serum albumin." Molecular pharmacology 11.6 (1975): 824-832.

Lemaire, Michael, et al. "Lipoprotein binding of drugs." Drug–protein binding (1986): 93-108.

Ehrnebo, M. "Drug binding to blood cells." Drug-protein binding, Praeger Pub., New York (1986): 128-137.