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(d) TISSUE LOCALIZATION: The tissue binding of drugs are also very significant processes occurring in the body. Unlike HSA, the body tissues constitute100 times that of HAS i.e.; about 40% of the total body weight. Multiple tissue drug binding are feasible. Tissue drug binding is very essential and vital process as it assists in enhancing the apparent volume of distribution for drugs as this follows a direct relation with the ratio of concentration of drug in body to-free or unbound drug in plasma. Also it results in prolonged duration of action due to increase in half-life reason being the localization of drug at a specific site in the tissues. Studies also reveal that a very large population of drugs no matter acidic, basic or neutral undergoes reversible binding whereas the plasma protein drug binding exhibits vice-versa. The order of binding to extravascular tissues is given as: 1. Liver> Kidney> Lung> Muscle. Lets have an overview of some tissue drug binding. Liver: Irreversible binding of drugs like paracetamol and their epoxide-metabolites to liver tissues results in hepatotoxicity.
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Intersubject variations:
Intersubject variability in drug binding as studied with few drugs showed that the difference is small and no more than two fold. These differences have been attributed to genetic and environmental factors.
Disease states:
The alterations in protein content and thereby the rate and extend of protein binding is greatly influenced by the albumin which is the major drug binding protein. This may ultimately lead to hypoalbuminemia which eventually with the pace of time completely impairs the entire protein drug binding process. For such situations the basic pathological conditions of diseases like trauma, burns, renal, cardiac or hepatic failure etc.. are largely responsible. Pharmacokinetics as well as Pharmacodynamic of drugs greatly influences the distribution, clearance and thus the biotransformation of drugs to a greater extend. Usually an increased potential of toxicity is observed due to increased concentration of free or the unbound drug. Putting in a nut shell, all factors, drug interactions and patient related factors that affect protein binding o tissue binding of drugs influence: (1)Pharmacokinetics of drugs. (2)Pharmacodynamics of drugs.
(1)Absorption:
The absorption equilibrium is attained by transfer of free drug from the site of administration into the systemic circulation and when the concentration in these two compartments become equal. Following equilibrium, the process may stop6.
(3)Distribution:
Plasma protein binding restrict the entry of drugs that have specific affinity for certain tissues. This prevents accumulation of a large fraction of drug in such tissues and thus, subsequent toxic reactions. Plasma protein-drug binding thus favours uniform distribution of drugs throughout the body by its buffer action1.
(4)Elimination:
Only the unbound or free drug is capable of being eliminated. This is because drug-protein complex cannot penetrate into the metabolizing organ. The large molecular size of the complex also prevents it from getting filtered through the glomerulus. Thus, drugs which are more than 95% bound are eliminated slowly i.e. they have long elimination half-lives.
(6)Diagnosis:
The thyroid gland has great affinity for iodine containing compounds; hence any disorder of the same can be detected by tagging of such a compound with a radioisotope of iodine.
CONCLUSION:
Drugs widely used in clinical pharmacology, with few exceptions, are hepatically eliminated and circulate in the blood bound to plasma proteins. Often, the degree of binding is high (>90%). This fact has led to a widespread belief that such drugs may frequently participate in drug-binding interactions. The logic is as follows: Co-administration of drugs can result in a highly bound drug displacing a less avidly bound drug from its binding sites. This leads to greater amounts of free, nonprotein-bound, drug available for distribution to the sites of action. As free drug is a major determinant of pharmacologic effects, these drug interactions could result in toxicity and/or enhanced efficacy. This reasoning simplifies a complex situation where compensatory changes occur in the body to buffer the impact of drug-binding interactions. There are few examples where the above events have been documented to occur with drugs leading to substantial clinical consequences. Although protein-binding displacement interactions are generally of minimal clinical significance, this is an assumption not based on evidence, but rather the lack of it7.
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REFERENCES:
(1) Brahamnkar.D.M,
Jaiswal.B.Sunil
In
Textbook
of
Biopharmaceutics
and
Pharmacokinetics, Edition I, Vallabh Prakshan, Delhi, 110088, 16-51. (2) Wagner, J.G.: Biopharmaceutics and Relevant Pharmacokinetics, Washington, D.C, Drug I (3) Sharjel, L.Yu, A.B.C.: Applied Biopharmaceutics and Pharmacokinetics, 2nd edition, Connecticut, Appleton Century Croffts, 1985ntelligence Publications, 1971. (4) Niazi, S.: Textbook of Biopharmaceutic and Clinical Pharmacokinetics, New York, Appleton Century Crofts, 1979. (5) Reindenburg, M.M. and Erill, S.: Drug-Protein Binding, New York, Praeger, 1986. (6) Mc Elany, J.C.: Buccal Absorption of Drugs. In: Encyclopedia of Pharmaceutical Technology, vol. 2(Swarbick, J. and Boylan, JC.,eds.), New York, Marcel Dekker, Inc., 1990. (7) Mayershon, M.: Principles of Drug Absorption. In.: Modern Pharmaceutics, 2nd edition.