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| Year : 1977 | Volume
: 23
| Issue : 2 | Page : 50-52 |
Drug protein binding: Relevance to treatment
Nilima A Kshirsagar, UK Sheth
Department of Pharmacology/Clinical Pharmacology, Seth G. S. Medical College, Parel, Bombay-400012, India
Correspondence Address:
Nilima A Kshirsagar
Department of Pharmacology/Clinical Pharmacology, Seth G. S. Medical College, Parel, Bombay-400012
India
 Source of Support: None, Conflict of Interest: None  | Check |
PMID: 614414 
How to cite this article:
Kshirsagar NA, Sheth U K. Drug protein binding: Relevance to treatment. J Postgrad Med 1977;23:50-2 |
Drug protein binding has attracted the attention of many investigators. The recognition or presumption of importance of protein binding and the ease of measuring drug protein interactions have led to accumulation of extensive literature in this field. This literature should be evaluated however from the point of clinical relevance. The pharmacological actions of drugs are produced in many instances due to binding to protein molecules. Binding to nonaction sites such as plasma proteins or tissue proteins also has pharmacological implications as it affects rates of absorption, distribution and excretion, can lead to allergic and toxic reactions and displace endogenous substances. [1],[3]
For a great majority of drugs serum albumin is quantitatively the most important plasma protein. Globulin, lipoproteins and erythrocytes form other sites of binding. Albumin has a net negative charge at physiological pH but can interact with both positive and negative charges on drugs. Although the earliest attraction and specificity of orientation of a drug molecule towards its binding site on albumin may be an electrostatic one, this interaction is reinforced by hydrogen bonds, hydrophobic bonds, Van der Wall's and covalent bonds. [5]
Several methods have been used to study drug protein binding. Equilibrium dialysis, gel-filtration and the ultrafiltration are the commonly used methods. Spectroscopic techniques like ultraviolet and visible absorption spectroscopy, circular dichroism etc. have also been used. These recent advances in methodology may result in important new information. In vitro studies of drug albumin interaction would be useful to establish extent of drug binding, number of binding sites and their affinities for drugs. Use of a scatchard plot can give some idea regarding these. Our study with propranolol has demonstrated the presence of two binding sites-a low affinity high capacity and a high affinity low capacity site (unpublished). In vitro studies should however be extrapolated to clinical situation cautiously, because these studies are conducted often under unphysiological conditions. As art alternative to in vitro measurement of plasma protein drug binding, for drugs that are not transported actively, a good index of their binding in serum is the difference between total drug concentration in serum and drug concentration in protein poor body fluids such as CSF or saliva.
The importance of drug protein binding to pharmacokinetics is on account of the fact that it is only the free fraction that can diffuse across capillaries and hence is available for action. Only free fraction is available for filtration and excretion or metabolism by passive processes. However, both free and bound fractions are available for metabolism and excretion when active transport processes are involved for e.g. propranokal [2] and penicillin [6] respectively.
There appears to be a general tendency to overemphasize importance of drug plasma protein binding. A doubling of free fraction in plasma is thought to lead to doubling of pharmacological effect. It should however be remembered that plasma volume and drug bound to protein usually form only a small part of the total drug in the body. Tissue volume of distribution is fairly large for most drugs. Hence any increase in free fraction in plasma gets diluted out as it equilibrates with tissues. It is only for drugs that have low tissue volume of distribution, a high per cent binding and low margin of safety that protein binding and displacement are important determinants of its action and toxicity. Thus although many drugs are highly protein bound, only a few satisfy all the three criteria, e.g., tricyclic antidepressants have large volume of distribution, penicillins have a wide therapeutic margin of safety. [6] As a result clinically important interactions indeed form a much smaller list than the number of in vitro experiments. Controlled quantitative studies of possible consequences of displacement interactions may lengthen the list in future.
What are the implications of the displacement interactions in terms of drug therapy? When a displacing drug is added to previous therapy with a protein bound drug there is an initial increase in free fraction, an increased distribution of the drug and an increase in pharmacological effect. As steady state is reached, however, because of increased elimination the plasma concentration falls and free fraction decreases to original level (but is now a larger fraction of the total), the pharmacological effect coming down to previous level. Thus in terms of drug therapy this means one should decrease the dose of a protein bound drug initially when a displacing drug is to be added to therapy. At present however it is difficult to predict accurately the necessary timing and extent of dosage changes which will depend also on whether drug has a slow onset of action and has active metabolites etc. [6] Titration of dosage by measuring clinical response and anticipating the change is still (!) the indicated procedure.
Besides drug interaction disease may affect binding. Lower plasma proteins due to malnutrition, cirrhosis or renal failure, altered configuration of protein, presence of high concentrations of substances like bilirubin, free fatty acids may affect binding. The quantitative effect of these on the extent of binding varies greatly among drugs. Epidemiologic studies have shown that adverse reactions to prednisone, phenytoin and diazepam are more common in hypoalbuminic patients. [4] The result of lowered binding is an increase in free fraction and this becomes particularly important when one is trying to adjust dosage by monitoring blood levels. This is because most of the available methods of drug assay estimate the total drug, but free fraction is actually the fraction available for action and since that is higher, a toxic effect may occur.
It thus appears on the whole that while considerable advances are being made in terms of studying the drug protein interaction at molecular levels, the implications of these in clinical practice are yet not fully understood. Effect of disease on binding is being extensively studied. The recognition that free drug is available for action and hence estimation of total drug in plasma can be misleading has led to development of assays to measure drug in protein free fluids like saliva or CSF. Computer models are being developed to predict dosage regimens from data on affinity constant for binding, volume of distribution etc. The limitations of these models still preclude their use and clinical response to drugs does remain still a major guideline in adjusting dosage in most situations in practice.
| :: Acknowledgements | |  |
The propranolol protein binding studies were done at Searle Research Centre, High Wycombe U.K., while one of the authors (N.K.) was working as a Searle Research Fellow. We acknowledge the assistance of the staff at Searle Research Centre.
| :: References | | |
| 1. | Chignell, C. F.: Spectroscopic techniques for the study of drug interactions with biological systems: Advances in Drug Research., 5: 55-94, 1969.  |
| 2. | Evans, G. H., Nies, A. S. and Shand, D. G.: The disposition of propranolol: III: Decreased half life and volume of distribution as a result of plasma binding in man, monkey, dog and rat. J. Pharmac. & Exper. Ther., 186: 114-122, 1973. |
| 3. | Gillette, J. R.: Overview of drug-protein binding: Ann. New York. Acad. Sci., 226: 6-17, 1973. |
| 4. | Greenbalt, D. J. and Koch-Weser, J.: Clinical toxicity of chlordiazepoxide and diazepam in relation to serum albumin concentration: a report from the Boston Collaborative Drug Surveillance Program. European J. Clin. Pharmac., 7: 259-269, 1974. |
| 5. | Koch-Weser, J. and Sellers, E. M.: Binding of drugs to serum albumin (first of two parts). The New Eng. Med., 294: 311316, 1976. |
| 6. | Koch-Weser, J. and Sellers, E. M.: Binding of drugs to serum albumin (second of two parts)., The New Eng. J. Med. 294: 526-531, 1976. |
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