Metabolites – Excretion and Elimination of Toxicants and their Metabolites
The first topic covered by this chapter was the excretion of wastes by the renal system. The first step that occurs in the kidney deals with the nephron, which is the functional unit of the kidney. In the glomerulus, the formation of urine begins with the passive filtration of plasma through the pores found in the glomerulus. The plasma is forced through these pores by hydrostatic pressure. The only thing that determines if a molecule will pass through the pores of the glomerulus is its molecular weight. The lower the molecular weight, the easier it will pass through the pores.
Another determining factor will be if a molecule is bound to a large molecule. If this is true, then passage through the pores will be hindered by the size of the larger molecule. Reabsorption of the many ions, minerals, and other nutrients that escaped in the glomerular filtrate will need to be recovered. Reabsorption begins in the tubules of the nephron. Anywhere from 65% to 90% of reabsorption occurs in these structures. Active reabsorption is used to recapture glucose, proteins, amino acids, and other nutrients. Water and chloride ions are passively reabsorbed by the establishment of osmotic and electrochemical gradients. Both the Loop of Henle and collecting duct are used to establish these osmolar gradients. The tubule has a brush border that will absorb proteins and polypeptides through pinocytosis. These molecules are sometimes catabolized and converted into amino acids and returned to the blood. Sometimes the accumulation of these proteins can lead to renal toxicity.
A second process that occurs in the tubules is tubular secretion. This is another mechanism used to excrete solutes. Secretion may be either passive or active. Secretions include organic bases, which occur in the pars recta of the proximal tubule. Secretions of weak bases and two weak acids occur passively. Other mechanisms involve the use of a mechanism that is called ion trapping. At a certain pH, the compounds are more ionized. Outside of the tubule, these compounds are non-ionized and are lipophilic. Thus they are able to diffuse across the membranes of the tubule. Once inside, the pH of the tubule will ionize them and render them unable to pass across the cell membranes.
The removal of xenobiotics is dependent on many factors. First is the polarity of the xenobiotic. Polar compounds are soluble in the plasma water and are more easily removed by the kidneys through the use of glomerular filtration. The faster the rate of glomerular filtration, the faster the polar xenobiotics are eliminated from the body. Other factors that affect the rate of elimination include the dose of the xenobiotic, the rate of absorption, and the ability to bind to proteins, as well as the polarity of the compound.
In comparison, lipophilic compounds will cross the cell membrane with more ease. Due to their lipophilic properties, they will follow their concentration gradient across the membrane of the tubules and are, therefore, easily retained by the body. If a lipophilic compound is metabolized to a more polar state, then it is more easily metabolized. Another important factor that will determine excretion by the kidneys will be the pH of the environment. Those compounds that are affected by pH will have both an ionized and nonionic form.
When in their non-ionized form, they will be reabsorbed by the tubules and kept there because of their change to an ionized form. The liver is the second most important organ involved in the removal of wastes from the body. The primary method of excretion involves the hepatic cells of the liver. Both passive and active modes of transport are used.
Bile is excreted by the hepatic cells. It is a concentration of amphipathic compounds that will aid in the transport of lipids from the small intestine. Before reaching the small intestine, via the common bile duct, it will be stored and concentrated in the gall bladder. The bile will then be reabsorbed by a process known as enterohepatic circulation. The more lipophilic or non-ionized a compound is, the more readily it will be absorbed.
Solubility is another factor that will determine absorbance. The rapid absorbance of these compounds does not mean that they will not be readily excreted. Some compounds are readily excreted after absorption. Most toxic xenobiotics are very lipophilic. This means that they will be easily absorbed and dispersed among the tissue.
Their lipophilic characterizations also mean that their excretion in either the urine or bile will be in very small amounts, unless they are metabolized into more polar compounds. One of the methods used to dispose of toxic lipophilics is by degradation of the large compounds into small polar fragments that can be eliminated through the urine or bile. Oxidative metabolism of toxic cyclic and polycyclic hydrocarbons is done with the introduction of a hydroxyl group into the ring structure. The excretion of halogenated hydrocarbons is extremely difficult. Their accumulation in the body occurs in both adipose tissue and lipid layers of the skin.
They will stay there for the duration of the animal’s lifetime. The molecular weight of a compound will determine if the compound will be excreted in the urine or feces. Any elimination of a xenobiotic will be done in association with the excretion of another compound that is normally eliminated by the body. Most gaseous and volatile xenobiotics are eliminated through the lungs. The rate of excretion is based on how soluble the compound is in the blood, the rate of volume of respiration, and the rate of blood flow to the lungs. A second method used is the alveolobronchial transport mechanism, which will involve the use of the mucociliary bronchotracheal escalator that will end with the material being swallowed and passed out of the body. Sex-linked elimination is restricted to the female. The milk excreted by the mother will contain the largest number of possible xenobiotics. The elimination of the xenobiotic is dependent on the half-life of the compound.
Most of the compounds that are excreted are low in dosage and therefore are not lethal. Chronic exposure can be toxic to the nursing young. The type of materials that are excreted are lipophilic because they are not excreted by the other major pathways. In eggs, the type of compound eliminated is also lipophilic in nature.
Fetuses are mostly affected by lipophilic compounds that are able to pass the placental barrier. There are cases of fatal exposure of xenobiotics to the fetus through the mother.