5/6/2023 0 Comments Red herring fallacy 2016Understanding how drugs like warfarin (fraction unbound f u= 0.01) bind to plasma proteins can help understand what happens if a drug (e.g., naproxen) that also binds to plasma proteins and can displace warfarin from its plasma protein binding site is given. The loading dose calculated from the apparent volume will be the same as long as the target concentration type (total or unbound) matches with the apparent volume type (total or unbound).īased on total drug concentration the apparent volume of distribution will be small when there is extensive binding to plasma proteins. If the plasma protein binding fraction remains constant then it does not matter if total or unbound concentrations are used. The ideal way to measure drug concentration is in the unbound form but this method is technically demanding, less precise and often a lot more expensive. The apparent volume will vary according to whether total or unbound drug is used for the calculation. Which is the correct apparent volume 10 L or 1000 L? But based on unbound concentration it is 1000 L. Based on total warfarin concentration the apparent volume of distribution is 10 L. About 99% of warfarin in plasma is bound to albumin leaving only 1% unbound. Warfarin is extensively bound to plasma proteins. A higher concentration in the sample leads to a lower apparent volume of distribution. The 'red herring' effect is caused by drug binding to plasma proteins. The concentration of drug will be higher in the sample than in the rest of the bath water because of the higher concentration of drug bound to the 'red herrings'. When a sample of bathwater is removed it also takes 'red herrings' with it. Imagine there are 'red herrings' swimming in the bathwater ( Fig. This gives a misleading impression of the volume of distribution and this phenomenon can be thought of as a 'red herring'. Because they bind to plasma proteins they are extracted from plasma and included in drug concentration measurements. Drugs bind to proteins like albumin and α 1-acid-glycoprotein. But binding to plasma will lead to a smaller apparent volume. Plasma protein binding is another major reason why the apparent volume of distribution does not correspond to a physical volume. All these substances will have relatively large volumes of distribution. radioactive caesium, are adsorbed to bone and can cause bone cancer. Bisphosphonate adsorption can be beneficial in osteoporosis by reducing bone breakdown. Tetracycline causes teeth staining in children. Partitioning into fat can make the apparent volume of distribution larger in obese people. Some drugs may have a large apparent volumes because of partitioning rather than binding to tissues. The apparent volume of distribution will be large when there is extensive binding to tissue proteins. The bathtub with sponge model of volume of distribution. Because the measured concentration is lower, the apparent volume must be larger than the physical volume. When drug concentration is measured in the water, it will be lower than it would have been if it was uniformly distributed in the tub (e.g. The binding of digoxin to Na +/K + ATPase is analogous to a drug being put in a bathtub and binding to a sponge in the water ( Fig. It happens that Na +/K + ATPase is also the site of action of digoxin therefore digoxin is unusual in this regard. This enzyme is essential for all cells and is found in large quantities in muscle, nervous tissue and the kidneys.īinding to tissue receptors that are also the site of action typically contributes only a small amount to the overall tissue distribution of most drugs. Digoxin binds extensively to Na +/K + ATPase. Typical values are 5 L for blood volume (2.5 L plasma, 2.5 L cells), 18 L for extracellular volume, and 50 L for total body water.Īpparent volume of distribution does not necessarily correspond to any physical compartment because of binding to tissues, binding to plasma proteins, preferential partitioning into fat or adsorption onto bone.Īn important example of tissue binding is for the drug digoxin. Molecules which can readily cross cell membranes may share the same physical volume as water. highly ionised molecules) will mainly be in the extracellular compartment. Molecules which can leave the vascular space but do not cross cell membranes easily (e.g. This vascular volume consists of the total blood volume, the fluid component defined by plasma and the cellular component defined largely by red blood cells. Very large molecules (proteins) or blood components (blood cells) will largely be confined to the vascular volume. It is common to distinguish 3 physical volumes based on anatomical and physiological concepts. In this example there is no loss of water from the bathtub.īy putting a known amount of drug (the dose) into the bathtub and measuring the concentration it is easy to calculate the apparent volume. The bathtub model of volume of distribution.
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