An introduction to principles of veterinary clinical pharmacology: The elimination of drugs

Abstract

Extract

Drug elimination refers to all the processes that operate to reduce the effective concentration of drug in the body fluids. Metabolism, storage and excretion are the three mechanisms whereby drugs are ultimately removed from their sites of action. Most drugs undergo metabolic transformation in the body — i.e., biotransformation — to more polar products with diminished or no activity. The principal site of drug biotransformation is the liver. However, biotransformation may also take place to varying extents in other tissues, including the intestinal mucosa, the blood plasma and the renal epithelium, and by the action of gut microflora. The most common pathways of drug metabolism involve oxidation, reduction, hydrolysis and conjugation. Very often a drug is subjected to several competing pathways simultaneously, and the extent of formation of the various metabolites depends on the relative rates of the various metabolic processes. In addition, metabolic reactions frequently proceed sequentially; oxidation, reduction), or hydrolysis reactions are followed by conjugation of products of the initial reaction. Numerous factors may influence the metabolism and, consequently, the activity of a chemical agent. These factors include dose and frequency of administration of the drug, species and strain of animal, route of administration, diet and nutritional status, liver and kidney function, age of animal, time of day, chronic administraton and the previous or concurrent administration of, or exposure to, certain chemical agents that may inhibit or induce important metabolic processes. The effects of biotransformation are complex. Usually the metabolites formed are more polar, less lipid-soluble, more ionized at physiological pH values, and are distributed in a smaller volume than the parent drug. For these reasons drug metabolism frequently leads to an accelerated termination of pharmacological activity. Often, metabolic alteration of structure is a prerequisite, to efficient clearance by the excretory organs. Many drug conjugates are excreted into urine and bile by carrier-mediated transport mechanisms which allow foreign compounds to be cleared very rapidly from plasma. Deposition and storage of drugs in, fat depots, in the reticuloendothelial system and in bone play significant roles in the removal from the circulation of lipid-soluble agents, colloidal substances and heavy metals, respectively. Removal of unchanged drug from the body via the kidney is the principal route of elimination of drugs that are water-soluble; this includes organic electrolytes that are predominantly ionized at the physiological pH reaction. The excretion rate of a drug depends upon the volume of distribution and extent of plasma protein binding of the drug and the following renal factors: glomerular filtration rate, extent of non-ionic back-diffusion of the drug from glomerular ultrafiltrate to blood plasma (pH and pK_a dependent) and degree of carrier-mediated excretion or reabsorption by the renal tubules. Variation in each of these factors can produce clinically significant changes in action of certain drugs, but changes in glomerular filtration rate will alter significantly the duration of action of all drugs that are eliminated from the body mainly by renal excretion. A drug may be excreted by the liver cells into bile and then pass into the intestine. Species variation in the extent of bilary excreton of drugs is likely to occur with compounds of molecular weight between 300 and 500 (Williams, 1971). The main importance of the biliary route of excretion is for the elimination of certain organic anions and cations that cannot be reabsorbed from the intestine because they are ionized at the intestinal reaction. It is evident that comprehensive appreciation of what occurs followng drug administration to either man or animals is possible only when pharmacokinetic analyses complement pharmacodynamic studies.