Excretion of Xenobiotics
The primary route for the excretion of xenobiotics and their metabolites are through urine and bile but they can also be excreted in the expired air, sweat, saliva, milk, vaginal secretions and by secretion into the stomach and other parts of gastrointestinal tract.
Kidneys are the primary route of excretion of xenobiotics and their metabolites from the body. Renal excretion occurs by three different mechanisms, that are glomerular filtration, active tubular secretion of ionized substances and passive tubular reabsorption of unionized substances.
The glomerular filtration produces an ultra-filtrate of the body plasma that contains xenobiotics and their metabolites approximate in same concentration as in the blood. After filtration, the chemical may remain within the tubular lumen and can be excreted or it may be passively reabsorbed across the tubular cells of the nephron into the blood stream. Reabsorbed molecules do not appear in the urine to any extent. Lipid-insoluble ionized molecules are the conjugates of xenobiotics and are poorly re-absorbed and are thus more readily excreted than their precursors through the kidney.
Toxic chemicals or xenobiotics can also be excreted from the plasma by passive diffusion through the tubule into the urine. Tubular epithelium behaves as a lipoprotein barrier and allows the transfer of lipid-soluble non-ionised molecules. Compounds that are highly ionized in the urine than in the blood plasma tend to diffuse across the tubular epithelium from the blood into glomerular filtrate. Thus when the tubular urine is more alkaline than plasma, weak acids are transferred into the urine, and conversely weak bases are transferred when the tubular urine is more acidic. Therefore, the rate of renal excretion of weak organic electrolytes is largely dependent on the pH of urine. The xenobiotics can also be excreted into urine by active tubular secretion. Organic anions (acids) and organic cations (bases) both are excreted through renal excretion. Actively secreted anions include chemicals such as p-aminohippuric acid, penicillin G, probenecid and chlorothiazole, whereas cations include hexamethonium, tetraethylammonium and N-methyl-nicotinamide. Substances secreted by the same active transport mechanism compete for each other and the excretion rate of one compound may be reduced by administration of another compound. For example, probenecid and carinamide compete with each other in excretion of penicillin. In newborn infants, especially the premature ones, many functions of kidney are not eliminated as rapidly and thus are more toxic in newborn than in adult.
The blood from gastrointestinal tract goes through liver before reaching for general systemic circulation. Liver can remove the chemicals from blood and prevent their distribution to other parts of body. Liver is the site of metabolism of most compounds, therefore, the particular chemical and its metabolites may be excreted directly into the bile without re-entering the blood stream to be excreted by renal system. The biliary route of excretion plays important function in elimination of anions, cations and non-ionised molecules. During these processes, the chemicals enter the bile primarily through active secretion. Brompsulfalein (BSP) is used since long as a test of liver function and is an example of organic anions transport. The removal of BSP is depressed after liver injury. Organic cations like ethobromide drug is also secreted by liver. Non-ionised molecules are also secreted in bile and perhaps liver has also a transport system for the excretion of metals.
Biliary excretion of xenobiotics varies with species to species, and is generally maximum in dog and rat. Hepatic excretory system is not fully developed in infants and therefore, some compounds are more toxic to infants than adults.
Gastrointestinal Tract (GIT)
Many compounds are excreted in the faeces. The excretion may be due to the agent or compound that are not absorbed after oral ingestion, either excreted into the bile or it is excreted by the gastrointestinal tract (GIT). Some ionized xenobiotics may be excreted into the gut, if concentration gradient is favourable.
Many of the volatile compounds are excreted unchanged in the expired air (air released during expiration). For example, flurobenzene, CO and some alcohols etc. are excreted by this route. Gases with a low blood/gas solubility such as benzene and nitrous oxide are excreted at rapid rates.
Chemicals are generally excreted through sweat in very small amounts. However, diethyl dithiolisophthalate, a drug used for treating leprosy is largely excreted in the sweat.
Some sulfonamides are excreted in the parotid saliva of man. Other drugs, such as pentobarbitone are excreted in higher concentration in the saliva of ruminants which is alkaline.
There are certain xenobiotics that are partly excreted into milk of lactating mammals. Since milk is more acidic, chemicals are excreted by simple diffusion than in plasma. Several compounds as DDT, thiouracil, tetracycline and erythromycin is also excreted in milk.
This route is not involved in the role of excretion of xenobiotics. Yet, hippuric and the glycine conjugate of benzoic acid have been reported in the estrus secretions of cow.
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