Foreign compounds excretion

The kidney is an important organ for the excretion of toxic materials and their metaboHtes, and measurement of these substances in urine may provide a convenient basis for monitoring the exposure of an individual to the parent compound in his or her immediate environment. The Hver has as one of its functions the metaboHsm of foreign compounds some pathways result in detoxification and others in metaboHc activation. Also, the Hver may serve as a route of elimination of toxic materials by excretion in bile. In addition to the Hver (bile) and kidney (urine) as routes of excretion, the lung may act as a route of elimination for volatile compounds. The excretion of materials in sweat, hair, and nails is usually insignificant. 

The metabolism of foreign compounds (xenobiotics) often takes place in two consecutive reactions, classically referred to as phases one and two. Phase I is a functionalization of the lipophilic compound that can be used to attach a conjugate in Phase II. The conjugated product is usually sufficiently water-soluble to be excretable into the urine. The most important biotransformations of Phase I are aromatic and aliphatic hydroxylations catalyzed by cytochromes P450. Other Phase I enzymes are for example epoxide hydrolases or carboxylesterases. Typical Phase II enzymes are UDP-glucuronosyltrans-ferases, sulfotransferases, N-acetyltransferases and methyltransferases e.g. thiopurin S-methyltransferase. 

Tubular secretion is the transfer of substances from the peritubular capillaries into the renal tubule for excretion in urine. This process is particularly important for the regulation of potassium and hydrogen ions in the body it is also responsible for removal of many organic compounds from the body. These may include metabolic wastes as well as foreign compounds, including drugs such as penicillin. Most substances are secreted by secondary active transport. 

The detoxification and excretion of xenobiotics (i.e., foreign compounds, including diet-derived allelochemicals) involve a suite of highly complex processes that allow an organism to respond to its internal and external chemical environments. Suchmetabolic resistance involves the biochemical transformation... 

Drugs must also be considered as foreign compounds, and an essential part of drug treatment is to understand how they are removed from the body after their work is completed. Glucuronide formation is the most important of so-called phase II metabolism reactions. Aspirin, paracetamol, morphine, and chloramphenicol are examples of drugs excreted as glucuronides. 

Renal elimination of foreign compounds may change dramatically with increasing age by factors such as reduced renal blood flow, reduced glomerular filtration rate, reduced tubular secretory activity, and a reduction in the number of functional nephrons. It has been estimated that in humans, beginning at age 20 years, renal function declines by about 10% for each decade of life. This decline in renal excretion is particularly important for drugs such as penicillin and digoxin, which are eliminated primarily by the kidney. 

The excretion of a foreign substance can also be a major factor in its toxicity and a determinant of the plasma and tissue levels. All these considerations are modified by species differences, genetic effects, and other factors. The response of the organism to the toxic insult is influenced by similar factors. The route of administration of a foreign compound may determine whether the effect is systemic or local. 

Although there are several sites of first contact between a foreign compound and a biological system, the absorption phase (and also distribution and excretion) necessarily involves the passage across cell membranes whichever site is involved. Therefore, it is important first to consider membrane structure and transport in order to understand the absorption of toxic compounds. 

Therefore, the pharmacokinetic parameters, which can be derived from blood level measurements, are important aids to the interpretation of data from toxicological dose-response studies. The plasma level profile for a drug or other foreign compound is therefore a composite picture of the disposition of the compound, being the result of various dynamic processes. The processes of disposition can be considered in terms of "compartments." Thus, absorption of the foreign compound into the central compartment will be followed by distribution, possibly into one or more peripheral compartments, and removal from the central compartment by excretion and possibly metabolism (Fig. 3.23). A very simple situation might only consist of one, central compartment. Alternatively, there may be many compartments. For such multicompartmental analysis and more details of pharmacokinetics and toxicokinetics, see references in the section "Bibliography." The central compartment may be, but is not necessarily, identical with the blood. It is really the compartment with which the compound is in rapid equilibrium. The distribution to peripheral compartments is reversible, whereas the removal from the central compartment by metabolism and excretion is irreversible. 

The rates of movement of foreign compound into and out of the central compartment are characterized by rate constants kab and kei (Fig. 3.23). When a compound is administered intravenously, the absorption is effectively instantaneous and is not a factor. The situation after a single, intravenous dose, with distribution into one compartment, is the most simple to analyze kinetically, as only distribution and elimination are involved. With a rapidly distributed compound then, this may be simplified further to a consideration of just elimination. When the plasma (blood) concentration is plotted against time, the profile normally encountered is an exponential decline (Fig. 3.24). This is because the rate of removal is proportional to the concentration remaining it is a first-order process, and so a constant fraction of the compound is excreted at any given time. When the plasma concentration is plotted on a logio scale, the profile will be a straight line for this simple, one compartment model (Fig. 3.25). The equation for this line is... 

The plasma half-life is another important parameter of a foreign compound, which can be determined from the plasma level. It is defined as the time taken for the concentration of the compound in the plasma to decrease by half from a given point. It reflects the rates at which the various dynamic processes, distribution, excretion and metabolism, are taking place in vivo. The value of the half-life can be determined from the semilog plot of plasma level against time (Fig. 3.25), or it may be calculated ... 

Another indication of the ability of an animal to metabolize and excrete, and therefore of the elimination of a foreign compound that can be gained from the plasma level data, is total body clearance. This may be calculated from the parameters already described ... 

Many toxic substances and other foreign compounds are removed from the blood as it passes through the kidneys. The kidneys receive around 25% of the cardiac output of blood, and so they are exposed to and filter out a significant proportion of foreign compounds. However, excretion into the urine from the bloodstream applies to relatively small, water-soluble molecules large molecules such as proteins do not normally pass out through the intact glomerulus, and lipid-soluble molecules such as bilirubin are reabsorbed from the kidney tubules (Fig. 3.31). 

Certain molecules, such as p-aminohippuric acid (Fig. 3.18), a metabolite of p-aminobenzoic acid are actively transported from the bloodstream into the tubules by a specific anion transport system. Organic anions and cations appear to be transported by separate transport systems located on the proximal convoluted tubule. Active transport is an energy-requiring process and therefore may be inhibited by metabolic inhibitors, and there may be competitive inhibition between endogenous and foreign compounds. For example, the competitive inhibition of the active excretion of uric acid by compounds such as probenecid may precipitate gout. 

Excretion into the bile is an important route for certain foreign compounds, especially large polar and amphipathic substances and may indeed be the predominant route of elimination for such compounds. 

Excretion into breast milk can be a very important route for certain types of foreign compounds, especially lipid-soluble substances, because of the high lipid content in milk. Clearly, newborn animals will be specifically at risk from toxic compounds excreted into milk. For example, nursing mothers exposed to DDT secrete it into their milk, and the infant may receive a greater dose, on a body-weight basis, than the mother. Also, because the pH of milk (6.5) is lower than the plasma, basic compounds may be concentrated in the fluid. 

Foreign compounds may be excreted into other body fluids such as sweat, tears, semen, or saliva by passive diffusion, depending on the lipophilicity of the compound. Although these routes are generally of minor importance quantitatively, they may have a toxicological significance such as the production of dermatitis by compounds secreted into the sweat, for example. 

Chasseaud LF. Processes of absorption, distribution and excretion. In Hathway DE, Brown SS, Chasseaud LF, et al. Foreign Compound Metabolism in Mammals, Vol. 1. London The Chemical Society, 1970. Findlay JWA. The distribution of some commonly used drugs in human breast milk. Drug Metab Rev 1983 14 653. 

In the biotransformation of foreign compounds, the body attempts to convert such lipophilic substances into more polar, and consequently, more readily excreted metabolites. 

The importance of the physicochemical characteristics of compounds has already been alluded to in the previous two chapters. Thus, lipophilicity is a factor of major importance for the absorption, distribution, metabolism, and excretion of foreign compounds. Lipophilic compounds are more readily absorbed, metabolized, and distributed, but more poorly excreted, than hydrophilic compounds. 

Distribution. The distribution of foreign compounds may vary between species because of differences in a number of factors such as proportion and distribution of body fat, rates of metabolism and excretion and hence elimination, and the presence of specific uptake systems in organs. For instance, differences in localization of methylglyoxal-bis-guanyl hydrazone (Fig. 5.6) in the liver account for its greater hepa to toxicity in rats than in mice. The hepatic concentration in mice is only 0.3% to 0.5% of the dose after 48 hours, compared with 2% to 8% in the rat. 

The rate of bile secretion and the pH of the bile may also be determinants of the extent of biliary excretion of a foreign compound, and these also show species variations. The fate of... 

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