Tissue binding of drugs

The distribution volume of some drugs also can be altered when renal function is impaired. As described in Chapter 3, Sheiner ef al. (27) have shown that impaired renal function is associated with a decrease in digoxin distribution volume that is described by the following equation  

This presumably reflects a reduction in tissue levels of Na/K-ATPase, an enzyme that represents a major tissue-binding site for digoxin (28). In other cases in which distribution volume is decreased in patients with impaired renal function, the relationship between the degree of renal insufficiency and reduction in distribution volume has not been characterized nor have plausible mechanisms been proposed. 

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Drug Distribution. After administration, a drug may be distributed either generally or selectively in the body. The distribution pattern depends on many factors, including the pattern and time-course of blood (low, diffusion of drugs into tissues, binding of drugs to plasma proteins and cellular compartments, and elimination kinetics and mechanisms. 

Oravcova J, Bohs B, Lindner W (1995) Drug-protein studies New trends in analytical and experimental methodology. Journal of Chromatography 677 1-28 Pacifici GM, Viani A (1992) Methods of Determining Plasma and Tissue Binding of Drugs. Clin Pharmacokinet 23(6) 449-468... 

Impaired renal function is associated with important changes in the binding of some drugs to -plasma proteins. In some cases the tissue binding of drugs is also affected. 

Pacific , G.M. Viani, A. Methods of determining plasma and tissue binding of drugs pharmacokinetic consequences. Clin. Pharmacokinet. 1994, 23, 449-468. 

Fichtl, B. Tissue binding of drugs methods of determination and pharmacokinetic consequences. In Plasma Binding of Drugs Belpaire, F., Bogaert, M., Tillement, J.P., Verbeeck,... 

This equation does not contain the expression /ut and, therefore, hepatic clearance is independent of changes in tissue binding of drug. 

These include absorption by adjacent palpebral and bulbar conjunctiva, with concomitant rapid removal from ocular-tissues by peripheral blood flow. For example, the extensive vascularity of the uvea underlies the bulbar conjunctiva, a mucous membrane, and the sclera, a white tissue providing a tough outer covering [177]. Binding of drug to either external sites, like the tear polymers such as mucins or lysozyme, or internal tissues like the sclera can be detrimental to efficacy. 

Binding of drug or drug-carrier conjugate to plasma proteins and various other non-target tissues [46,55], which potentially act as a slow release compartments (see Section 13.2.1.4). 

C) The binding of drugs to tissues has no relationship to the distribution of drug in the body. 

Paclitaxel s large volume of distribution indicates significant tissue binding. The drug is extensively metabolized by the liver, and doses must be reduced in patients with abnormal liver function or with extensive liver metastases. Very little of the drug is excreted in the urine. 

Tissue binding versus plasma binding of drugs General principles and pharmacokinetic consequences, 20, 117... 

Marked differences in the drug-binding capacity of plasma proteins exist among mammalian species. Variations in the plasma protein binding of drugs may contribute to the species differences in the tissue levels of the drugs, their toxicity, and overall kinetics, particularly if the binding is extensive. 

Many drugs have distribution volumes that exceed expected values for TBW, or are considerably larger than ECF despite extensive binding to plasma proteins. The extensive tissue binding of these drugs increases the apparent distribution volume that is calculated by reference to drug concentrations measured in plasma water. By modifying Equation 3.1 as follows. 

Tissue binding. Some drugs distribute readily to regions of the body other than plasma, as a glance... 

The extent and degree of interactions between chiral macromolecules of the body and stereoisomers is a source of observable differences in isomeric drug distribution. Stereoselectivity in drug distribution may occur when tissue or protein binding or uptake is associated with structurally specific receptor, protein, or enzyme binding. Since only unbound or free drug is susceptible to elimination and distribution to receptors and other tissues and fluids, differences in the protein and tissue binding of stereoisomers are reflected in their overall pharmacokinetic profiles. 

The binding of drugs to various body tissues appears to vary with age for example, digoxin binding to erythrocytes is higher in neonates than in adults. This may be due to the increased number of binding sties on neonatal erythrocytes. ... 

The binding of drug to tissue is usually reversible. In some cases, however, there is covalent binding, which by definition is not reversible. This applies to drug or metabolite and could be important because it could be related to toxicity. " A good correlation has been reported in animals between the degree of covalent binding to hepatic protein and the severity of hepatic necrosis of paracetamol, isoniazid, adriamycin, and furosemide. " ... 

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