Interactions Affecting Transport Metabolism and Excretion

Functional Synergism or Antagonism

The biological actions of nutrients and drugs can be synergistic or antagonistic, occur at different times after exposure, and affect a variety of target tissues. Some of the most common mechanisms are as follows.

Alterations in drug transport Drugs circulate in the bloodstream as free compounds or bound to other constituents, usually proteins. Drugs vary greatly in their propensity to bind to circulating proteins, covering virtually the entire spectrum from 0 to 100%. For a given drug, the bound fraction tends to be relatively constant under physiological conditions, but responds to changes in pH, electrolyte balance, and the presence of competing molecules. The major transport protein in plasma is albumin, and its concentration and the presence of other compounds with an affinity for albumin binding will affect the amount of drug that will ultimately be transported by this protein.

Increase in nutrient catabolism Certain drugs stimulate detoxifying systems, such as the cytochrome P-450 pathway. Activation of this system may result in increased catabolism of certain nutrients. In other cases, drugs directly affect nutrient catabolism, as in the case of anticonvulsant drugs, which stimulate vitamin D catabolism in the liver.

Changes in drug metabolism Certain nutrients (such as those found in grapefruit) can inhibit the activity of cytochrome P-450. Cytochrome P-450-3A is the only isoform affected in a clinically significant way. The mucosal cells of the small intestine are affected to a greater degree than the hepatic cyto-chrome P-450-3A. Certain HMG-CoA reductase inhibitors (statins), simavastin, and lovastatin can have a significant interaction with grapefruit juice.

Biological antagonism Biological antagonism occurs when drug and nutrient have opposite biological actions, as is the case, for example, with vitamin K and salicylates in the coagulation process.

Increased nutrient losses Many drugs directly or indirectly enhance the urinary excretion of nutrients. Examples are the increased urinary losses of electrolytes caused by aminoglycoside antibiotics and amphotericin B antifungals, and the increase in urinary ascorbic acid excretion induced by barbiturates.

Host-related Functional Interactions

Nutrients and nutritional status can also affect drug action and disposition. Perhaps the most significant host-related factor affecting drug disposition is protein synthesis. Altered protein synthesis, usually resulting from insufficient dietary protein intake or severe diseases, will affect absorption, transport, metabolism, and excretion, as these are all protein-dependent processes. The role of plasma albumin in drug transport was discussed above and will certainly be affected by impaired albumin synthesis and/or sequestration in the extravascular space, as seen in protein-energy malnutrition. It should be noted, however, that malnutrition affects many aspects of drug metabolism, not all in the same direction. For example, drug delivery may be reduced by impaired albumin concentration, but the drug concentration in the bloodstream may be increased as a result of impaired clearance, which is also affected by malnutrition.

The plasma amino-acid profile may affect the efficacy of drug entry into the central nervous system. At the blood-brain barrier, certain drugs are transported into the brain by the same transport system that carries the large neutral amino-acids; thus they must compete with them for use of the carrier binding sites. Diet composition, by affecting the postprandial amino-acid profile, may significantly affect the clinical efficacy of drugs such as L-dopa, used in the treatment of Parkinson's disease.

Body composition is also a relevant determinant of drug disposition and action. Although most drug dosages are calculated by total body weight, most drugs act only in the fat-free body mass. Thus, at a given body weight, individuals with more body fat will tend to receive a higher effective dose than those with less body fat. The amount of body fat is also important for drugs that are stored in adipose tissue.

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