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Secretion, which occurs in the proximal tubule section of the nephron, is responsible for the transport of certain molecules out of the blood and into the urine. Secreted substances include potassium ions, hydrogen ions, and some xenobiotics. Secretion occurs by active transport mechanisms that are capable of differentiating among compounds on the basis of polarity. Two systems exist, one that transports weak acids (such as many conjugated drugs and penicillins) and the other that transports basic substances (such as histamine and choline).
Reabsorption takes place mainly in the proximal convoluted tubule of the nephron. Nearly all of the water, glucose, potassium, and amino acids lost during glomerular filtration reenter the blood from the renal tubules. Reabsorption occurs primarily by passive transfer based on concentration gradient, moving from a high concentration in the proximal tubule to the lower concentration in the capillaries surrounding the tubule.
A factor that greatly affects reabsorption and urinary excretion is the pH of the urine. This is especially the case with weak electrolytes. If the urine is alkaline, weak acids are more ionized and thus excreted to a great extent. If the urine is acidic, the weak acids (such as glucuronide and sulfate conjugates) are less ionized and undergo reabsorption with renal excretion reduced. Since the urinary pH is variable in humans, so are the urinary excretion rates of weak electrolytes. Examples are phenobarbital (an acidic drug) which is ionized in alkaline urine and amphetamine (a basic drug) which is ionized in acidic urine. Treatment of barbiturate poisoning (such as an overdose of phenobarbital) may include changing the pH of the urine to facilitate excretion. Diet may have an influence on urinary pH and thus the elimination of some toxicants. For example, a high-protein diet results in acidic urine.
V. C. Scanlon and T. Sanders, Essentials of Anatomy and Physiology, 2nd edition. F. A. Davis, 1995.
It can be seen that the ultimate elimination of a substance by the kidney is greatly affected by its physical properties (primarily molecular size) and its polarity in the urinary filtrate. Small toxicants (both polar and lipid-soluble) are filtered with ease by the glomerulus. In some cases, large molecules (including some that are protein-bound) may be secreted (by passive transfer) from the blood across capillary endothelial cells and nephron tubule membranes to enter the urine. The major difference in ultimate fate is governed by a substance's polarity. Those substances that are ionized remain in the urine and leave the body. Lipid-soluble toxicants can be reabsorbed and re-enter the blood circulation, which lengthens their half-life in the body and potential for toxicity.
Kidneys, which have been damaged by toxins, infectious diseases, or as a consequence of age, have diminished ability to eliminate toxicants thus making those individuals more susceptible to toxins that enter the body. The presence of albumin in the urine indicates that the glomerulus filtering system is damaged letting large molecules pass through. The presence of glucose in the urine is an indication that tubular reabsorption has been impaired.
Elimination of toxicants in the feces occurs from two processes, excretion in bile, which then enters the intestine, and direct excretion into the lumen of the gastrointestinal tract. The biliary route is an important mechanism for fecal excretion of xenobiotics and is even more important for the excretion of their metabolites. This route generally involves active secretion rather than passive diffusion. Specific transport systems appear to exist for certain types of substances, e.g., organic bases, organic acids, and neutral substances. Some heavy metals are excreted in the bile, e.g., arsenic, lead, and mercury. However, the most likely substances to be excreted via the bile are comparatively large, ionized molecules, such as large molecular weight (greater than 300) conjugates.
Once a substance has been excreted by the liver into the bile, and subsequently into the intestinal tract, it can then be eliminated from the body in the feces, or it may be reabsorbed. Since most of the substances excreted in the bile are water soluble, they are not likely to be reabsorbed as such. However, enzymes in the intestinal flora are capable of hydrolyzing some glucuronide and sulfate conjugates, which can release the less polar compounds that may then be reabsorbed. This process of excretion into the intestinal tract via the bile and reabsorption and return to the liver by the portal circulation is known as the enterohepatic circulation.
The effect of this enterohepatic circulation is to prolong the life of the xenobiotic in the body. In some cases, the metabolite is more toxic than the excreted conjugate. Continuous enterohepatic recycling can occur and lead to very long half-lives of some substances. For this reason, drugs may be given orally to bind substances excreted in the bile. For example, a resin is administered orally which binds with the dimethylmercury (which had been secreted in the bile), preventing reabsorption, and further toxicity.
The efficiency of biliary excretion can be affected by changing the production and flow of bile in the liver. This can occur with liver disease, which usually causes a decrease in bile flow. In contrast, some drugs (e.g., phenobarbital) can produce an increase in bile flow rate. Administration of phenobarbital has been shown to enhance the excretion of methylmercury by this mechanism.
J. A. Timbrell, Principles of Biochemical Toxicology, Taylor & Francis LTD, London.
Another way that xenobiotics can be eliminated via the feces is by direct intestinal excretion. While this is not a major route of elimination, a large number of substances can be excreted into the intestinal tract and eliminated via feces. Some substances, especially those which are poorly ionized in plasma (such as weak bases), may passively diffuse through the walls of the capillaries, through the intestinal submucosa, and into the intestinal lumen to be eliminated in feces. Intestinal excretion is a relatively slow process and therefore, it is an important elimination route only for those xenobiotics that have slow biotransformation, or slow urinary or biliary excretion. Increasing the lipid content of the intestinal tract can enhance intestinal excretion of some lipophilic substances. For this reason, mineral oil is sometimes added to the diet to help eliminate toxic substances, which are known to be excreted directly into the intestinal tract.
The lungs represent an important route of excretion for xenobiotics (and metabolites) that exist in a gaseous phase in the blood. Blood gases are excreted by passive diffusion from the blood into the alveolus, following a concentration gradient. This occurs when the concentration of the xenobiotic dissolved in capillary blood is greater than the concentration of the substance in the alveolar air. Gases with a low solubility in blood are more rapidly eliminated than those gases with a high solubility. Volatile liquids dissolved in the blood are also readily excreted via the expired air. The amount of a liquid excreted by the lungs is proportional to its vapor pressure. Exhalation is an exception to most other routes of excretion in that it can be a very efficient route of excretion for lipid soluble substances. This is due to the very close proximity of capillary and alveolar membranes, which are thin and allow for the normal gaseous exchange that occurs in breathing.
Other Routes of Excretion
Several minor routes of excretion exist, primarily via mother's milk, sweat, saliva, tears, and semen. Excretion into milk can be important since toxicants can be passed with milk to the nursing offspring. In addition, toxic substances may be passed from cow's milk to people. Toxic substances are excreted into milk by simple diffusion. Both basic substances and lipid-soluble compounds can be excreted into milk. Basic substances can be concentrated in milk since milk is more acidic (pH ~ 6.5) than blood plasma. Since milk contains 3-4% lipids, lipid soluble xenobiotics can diffuse along with fats from plasma into the mammary gland and thus can be present in mother's milk. Substances that are chemically similar to calcium can also be excreted into milk along with calcium. Examples of substances that can be excreted in milk are DDT, polybrominated biphenyls, and lead (which follows calcium kinetics).
Excretion of xenobiotics in all other body secretions or tissues (including the saliva, sweat, tears, hair, and skin) are of only minor importance. Under conditions of great sweat production, excretion in sweat may reach a significant degree. Some metals, including cadmium, copper, iron, lead, nickel, and zinc, may be eliminated in sweat to some extent. Xenobiotics that passively diffuse into saliva may be swallowed and absorbed by the gastrointestinal system. The excretion of some substances into saliva is responsible for the unpleasant taste that sometimes occurs with time after exposure to a substance.
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