Absorption, Distribution, Metabolism, and Excretion of Toxic Agents in Animals

Absorption can occur through the GI tract, skin, lungs, eye, mammary gland, or uterus, as well as at sites of injection. Toxic effects can be local; however, the toxic agent must be dissolved and absorbed to some extent to affect the cell.

Solubility is the primary factor affecting absorption. Insoluble salts and ionized compounds are poorly absorbed, whereas lipid-soluble substances are generally readily absorbed, even through intact skin. For example, barium is toxic, but barium sulfate can be used for intestinal contrast radiography because of its low absorption.

Distribution, or translocation, of a toxic agent occurs via the bloodstream to tissues and organs, including storage depots, throughout the body. Storage depots, such as adipose tissue, can be protective or can worsen the potential for poisoning. The liver receives the portal circulation and is the organ most commonly involved with intoxication (and detoxification).

The selective deposit of foreign chemicals in various tissues depends on receptor sites. Ease of distribution depends largely on the water solubility of the chemical. Polar or aqueously soluble agents tend to be excreted by the kidneys; lipid-soluble chemicals are more likely to be excreted via the bile and accumulate in fat depots.

The highest concentration of a toxic agent within an animal is not necessarily found in the organ or tissue on which it exerts its maximal effect (the target organ). Lead, for example, can be found in highest concentrations in bone, which is neither a site for toxic effects nor a reliable tissue for toxicological interpretation.

Knowledge of the distribution characteristics of toxic agents is necessary for proper selection of tissues and organs to analyze when pursuing a diagnosis. Volume of distribution (Vd) is the total amount of substance in the body, divided by the concentration of the substance within the blood. It refers to xenobiotic distribution throughout the body. Substances with a low Vd have limited distribution and are contained within plasma; substances with a high Vd have an extensive distribution throughout the body.

Metabolism, or biotransformation, of toxic agents by the body is an attempt to detoxify. In some instances, metabolized xenobiotic agents are more toxic than the original compound (biosynthesis of a toxin from a nontoxic precursor is referred to as "lethal synthesis"). For example, ethylene glycol itself is not a toxic concern before it is metabolized; however, the metabolites produced by its metabolism, including glycolaldehyde, glycolic acid, glyoxylic acid, and oxalic acid, are responsible for ethylene glycol's various detrimental effects. Bromethalin metabolism by the liver also produces a more toxic metabolite, desmethyl bromethalin.

Reactions involved in the metabolism of xenobiotics historically have been divided into two classes.

• Phase I metabolism includes oxidation, reduction, and hydrolysis. These reactions, catalyzed by hepatic enzymes, generally convert foreign compounds to derivatives for phase II reactions. Products of phase I metabolism, however, can be excreted as such, if polar solubility permits translocation.

• Phase II metabolism principally involves conjugation or synthesis. Common conjugates include glucuronides, acetylation products, and combinations with glycine. Metabolism of xenobiotic agents seldom follows a single pathway. Usually, a fraction is excreted unchanged, and the rest is excreted or stored as metabolites.

Important differences in metabolic mechanisms exist between species. For example, because cats lack forms of glucuronyl transferase, their ability to conjugate compounds such as morphine and NSAIDs is compromised.

Increased tolerance to subsequent exposures of a toxic agent is sometimes due to enzyme induction initiated by the previous exposure. In the case of bromethalin, guinea pigs have a decreased ability to metabolize bromethalin into the more toxic compound desmethyl bromethalin, so they are more resistant than other species to bromethalin toxicosis.

Although excretion of most toxic agents and their metabolites occurs via the kidneys, there are many possible routes of excretion. Depending on the toxic agent, some excretion also occurs in the GI tract, milk, sweat, saliva, and CSF.

Hepatic elimination occurs for many substances through biliary elimination in the feces. Ibuprofen and most other NSAIDs are examples of substances eliminated through the bile and excreted in the feces. An enterohepatic cycle occurs when compounds are excreted from the liver via bile, reabsorbed from the intestine, and returned to the liver.

The route of administration and dose of the toxic agent, as well as the condition of the animal—to name a few factors—can have profound effects on excretion rates.

Toxic agents that are removed in the kidney are eliminated by means of glomerular filtration, tubular excretion via passive diffusion, and active tubular secretion. Damage to the kidney from the excretion of xenobiotics is specific to the anatomical location where excretion occurs. Excretion sites are the proximal tubules, glomeruli, medulla, papilla, and loop of Henle. The proximal convoluted tubule is the most common site of toxic injury.

The important phase I enzymes present in the kidney are cytochrome P450, prostaglandin synthase, and prostaglandin reductase. The phase I enzyme cytochrome P450 is present in the kidney at approximately 10% of the concentration found in the liver. Important phase II enzymes present in the kidneys are UDP-glucuronosyltransferases (UGTs), sulfotransferases, and glutathione-S-transferase.

The excretion rate is often of primary concern because it can affect the duration of clinical signs and treatment needs. Violative residues of toxic agents can occur in food-producing animals; knowledge of this possibility is important when determining the outcome of an animal product intended to enter the food chain.

The elimination or disappearance (by metabolic change) of a chemical from an organ or the body is expressed in terms of half-life (t), defined as the amount of time required for half of the compound to disappear. The rate of elimination usually depends on the concentration of the compound.

• The elimination of a constant fraction (eg, ½) of the total drug per unit of time is referred to as "first-order kinetics."

• The elimination of a constant absolute amount of the total drug per unit of time is referred to as "zero-order kinetics."

A metabolic reaction can dictate the rate of elimination. Different body compartments will likely have different elimination rates. In a two-compartment system, elimination is initially rapid (eg, from the central or plasma component) and subsequently slower (from the peripheral component—eg, liver, kidney, or fat).

• Peterson ME, Talcott PA, eds. Small Animal Toxicology. 3rd ed. Elsevier; 2013.

• Gupta RC, ed. Veterinary Toxicology: Basic and Clinical Principles. 3rd ed. Elsevier; 2018.

• Klaassen CD (ed.), Casarett LJ, Doull J. Casarett and Doull's Toxicology: The Basic Science of Poisons. 9th ed. McGraw-Hill; 2019.

• Also see pet health content regarding metabolism of poisons.