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Transcript
PROTEIN BINDING Interaction of Drug with Tissue Protein Interaction of Drug with Plasma Protein Tissue Protein Binding • Drug may bind reversibly with proteins • Some drugs are highly bound to tissue proteins • Free drugs penetrate cell membranes, distributing into various tissues including those tissues involved in drug elimination (kidney, liver) • Active renal secretion – carrier mediated system, may have a greater affinity for free drug molecul compared to plasma protein • In this case, active renal drug excretion allows for rapid drug excretion despite drug protein binding • Some models: the drug distributes from the plasma water into extracellular tissue fluid, where the drug binds to extravascular proteins, resulting in a relatively larger VD due to extracellular protein binding • Drugs with lower distribution to the extracellular water are more extensively distributed inside the tissues (Protein binding to tissue) and tend to have a large apparent volume of distribution • Binding of drugs by tissue may necessitate a larger initial bolus to achieve the desired effect (the concentration in receptor large enough to give pharmacological effect) • Large depots of drug in tissue may necessitate a longer period of time for drug to be removed from the body • An excessively high VD (>body volume of 70 L) is due mostly to special tissue storage, tissue protein binding, carrier, or efflux system which removes drug from the plasma fluid : Digoxin, is bound to myocardial membrane • The high tissue binding is responsible for the large steady state volume of distribution • The greater drug affinity also results in longer distribution α half-life in spite of the heart’s great vascular blood perfusion • Imipramin is highly protein bound and concentrated in plasma, yet its favorable tissue partition and binding accounts for a large volume of distribution. • TCA (Tri Cyclic Antidepressants– large volume of distribution due to tissue (CNS) penetrating and binding • The accumulation of drug into tissues is dependent on:- the blood flow - the affinity of the drug for the tissue • The drug concentration in a tissue with low capacity equilibrates rapidly with the plasma drug concentration and then declines rapidly as the drug is eliminated • Drugs with high tissue affinity tend to accumulate or concentrate in the tissue • Drugs may accumulate in tissue by binding to proteins or other macromolecules in a tissue • Drug accumulate in tissue - binding to protein tissue: Digoxin – highly binding to protein in cardiac tissue – leading in a large volume of distribution ( 440 L / 70 kg) and long t1/2 (40 hrs) • Some drugs complex with melanin in the skin and eye after long term administration of high doses of phenothiazine to chronic schizophrenic patients • Tetracycline – forms an insoluble chelate with calcium on teeth and bones • Amphetamin (phenilethylamine structure) ≈ norepinephrine, is actively transported into and accumulated in adrenergic tissue (a specific uptake system for catecholamin/ norepinephrine) Plasma protein Binding • Many drugs bind to circulating plasma proteins to form a drug-macromolecule complex or drug-protein binding by a reversible or irreversible process. Since these proteins are large, bound drugs cannot pass out of vascular space – thus plasma protein binding has the effect of restricting the distribution of drugs • As plasma protein binding increases, the extent of distribution decreases Irreversible drug protein binding • A result of the chemical activation of the drug, which then attaches strongly to the protein/macromolecule by covalent bonding • Accounts for certain types of drug toxicity occurred over a long time period – chemical carcinogenesis • Within relatively short time period – drugs that form reactive chemical intermediates : hepatotoxic of high dose of paracetamol is due to the formation of reactive metabolite intermediates that interact with liver proteins Reversible drug-protein binding • Large complex that cannot easily transverse cell or possibly even capillary membranes and therefore has a restricted distribution • Pharmacology inactive • Free/unbound drug crosses cell membranes and is therapeutically active • Studies is done in vitro using albumin purified protein including equilibrium dialysis and ultrafiltration using a semipermeable membrane that separates the protein and protein-bound drug from the free/unbound drug, and total protein may be determined, with advantage and disadvantage • Drugs may bind to various macromolecular components in the blood including albumin, α1acid glycoprotein, lipoproteins, immunoglobulins (IgG), and erythrocytes (RBC) • Effect of protein binding on the VD • Relation of plasma drug-protein binding to distribution and elimination • Relationship between VD and Drug elimination half life • Elimination of Protein-bound drug: Restrictive versus Nonrestrictive Elimination Methods for Studying Drug-Protein Binding • • • • • • • • Equilibrium Dialysis Dynamic dialysis Diafiltration Ultrafiltration Gel Chromatography Spectrophotometry Electrophoresis Optical Rotary Dispersion Circulatory dichroism Kinetics of Protein Binding