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Drug and Metabolite Excretion |  |
| The concentration of a drug in the plasma or at its receptor sites may be reduced in 3 ways: 1) distribution or redistribution into various tissue compartments, 2) metabolic inactivation, and 3) excretion from the body. The kidneys are the principal organ of excretion, but the liver, GI tract, and lungs also may play important roles. Milk, saliva, and sweat are usually of less importance, although the presence of an active drug in milk may affect nursing young. |
| Renal excretion of foreign compounds involves glomerular filtration, passive diffusion into and out of the tubular lumen, and carrier-mediated secretion, mainly in the proximal convoluted tubule. Only unbound molecules <66,000 daltons are readily filtered through the glomerular membranes into the tubular lumen. Acidification or alkalinization of the urine may alter the rate of excretion of some drugs because of ion-trapping in the tubular fluid. |
| Binding to plasma proteins usually does not hinder tubular excretion of drugs because of the dynamic equilibrium that exists between free and bound drug. As free drug is removed and transported across the tubular epithelium, immediate dissociation of the drug-albumin complex usually occurs. Concurrent administration of either acidic or basic drugs that are substrates for carrier-mediated secretion processes prolongs the elimination of the drug that has the lesser affinity for the
carrier sites, thus increasing its duration of action. |
| Drugs and their metabolites may also be excreted either passively or actively by hepatocytes into the bile canaliculi and, ultimately, into the duodenum in the bile. Drugs may become unconjugated by intestinal microflora. Released drug can be reabsorbed into the systemic circulation. Enterohepatic cycles often account for prolonged half-lives of drugs that are primarily excreted in bile. Impairment of the excretory functions of the hepatocytes or obstruction of bile flow due to any
cause interferes with the biliary excretion of drugs. Dose or interval should then be adjusted accordingly. The normal kinetics of a drug’s enterohepatic cycle may change in such cases, or may be modified by disruption or elimination of the intestinal flora. |
| The other routes of excretion are of lesser clinical importance. However, several drugs may diffuse directly into the GI tract and then be eliminated in the feces. The ruminoreticulum can act as a drug reservoir or “sink.” The tracheobronchial tree also may be a potential avenue of excretion. Many drugs that are administered parenterally are found in bronchial secretions. Alveolar elimination is of major significance when inhalant anesthetics are used. The main factors governing
elimination by this route are the same as those determining the uptake of inhalant anesthetics—the concentrations in plasma and alveolar air and the blood/gas partition coefficient. The mammary and salivary glands excrete drugs by nonionic passive diffusion. The salivary route of excretion is important in ruminants because they secrete such voluminous amounts of alkaline saliva. |
| If the excretory functions of those organs concerned with drug elimination are impaired or altered in any way (eg, disease, very young or very old animal), prolonged elimination patterns result. Moreover, several nutritional and pharmacokinetic interactions have the potential to change the rates of drug excretion. |
| When urinary excretion is an important route of elimination, renal failure results in decreased drug clearance and, thus, slower removal of the drug from the body. A usual dosage regimen in such cases tends to lead to accumulation and, ultimately, toxicity. A number of disturbances may occur within failing kidneys, all of which may influence the excretion of drugs: renal ischemia, glomerular involvement, tubular damage, impaired intrarenal perfusion, functional disabilities of the
tubular cells, failed homeostatic mechanisms, and obstructive lesions in the tubules or collecting ducts (or even the ureters or urethra). Changes in the pH of the filtrate also alter the excretion rates of drugs with appropriate pKa values. In addition to the direct effect on renal excretory mechanisms, pathologic changes in the kidneys can influence the disposition and elimination of drugs. In most instances, drug toxicity is increased. The binding of many
drugs to plasma proteins is decreased in uremic animals. The rate of metabolic reactions may be depressed in renal failure, impairing effective elimination of agents that require biotransformation. Associated clinical signs and pathophysiologic changes, often encountered in renal failure, can also alter pharmacodynamic responses to particular drugs. Derangements of acid-base balance, hyper- and hypokalemia, hyper- and hyponatremia, dehydration, and hyper- and hypotension are examples
of systemic conditions that may radically modify a drug’s fate or action. |
