General Principles Of Pharmacology:Sites of drug binding and its effect on drug distribution
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and explanatory notes their glomerular filtration
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Albumin and other plasma proteins are essentially contained within blood vessels, so bound drug, and is similarly restricted. When more than 70-80% of the drug in plasma is protein bound, it acts as a considerable reservoir for the drug. The effect of protein binding on the distribution of a drug between blood plasma and transcellular fluid (relatively protein-free) can be calculated.
Two or more different drugs may bind to the same site on plasma proteins. Thus, administration of a second drug may significantly affect the binding of the first drug. Changes in binding have the greatest effect on the proportion of free drug when the percent binding is high. Reducing binding from 98% to 96% will double the amount of free drug (2% to 4%). With only 60% bound, the reduction would have to be 20% to double the free drug (40% to 80%).
For example at its therapeutic concentration, the anticoagulant, warfarin, is 97.4% bound. If a therapeutic dose of the nonsteroidal antiinflammatory drug, phenylbutazone, is administered, bound warfarin decreases to 92%. Thus, free warfarin increases from 2.6% to 8% (3-fold). This increases the anticoagulant effect of warfarin considerably.
Drug disposition
Drug disposition deals with the interactions of foreign chemicals with protein targets on the surface of cell membranes as well as within cells, sometimes leading to toxic manifestations, but other times protecting normal cellular functions. Such chemicals include established and newly developed drugs, natural products such as dietary compounds, and manmade environmental contaminants. To enter the cell or the whole organism, including the human being, such chemicals must pass through membranes containing transporters, which either facilitate or prevent uptake. Although metabolic enzymes many times serve, in unison with transporters, as further protective barriers for the cell against foreign chemicals, sometimes such enzymes give rise to reactive metabolites, which form the basis for cytotoxic or carcinogenic actions. Some chemicals or their metabolites can induce oxidative stress in cells, whereas others can be protective. It is the balance between the healthy and harmful effects of these agents that determines whether the cell, or organism, will survive.
Next Page: Drug metabolism: some definitions
and explanatory notes their glomerular filtration
Previous Page: Drug Dilution in Body Water
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