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Find information on animal health topics, written for the veterinary professional.

Disposition and Fate of Drugs

By Dawn Merton Boothe, DVM, PhD, Professor, Department of Anatomy, Physiology, and Pharmacology, College of Veterinary Medicine, Auburn University

The goal of drug therapy is to achieve a pharmacologic response. The magnitude of the pharmacodynamic response to a drug generally reflects the number of receptors with which the drug interacts (drug-receptor theory). Because tissue drug concentrations generally parallel tissue concentrations, the ideal dose will result in plasma drug concentrations in a "therapeutic range." This population statistic is defined by a maximum drug concentration, above which the risk of adverse events (eg, toxicity) increases, and a minimum drug concentration, below which therapeutic failure may result. Plasma drug concentrations generally fluctuate during a dosing interval, because they are impacted by four drug movements acting simultaneously on the drug: absorption from the site of nonintravenous administration into the plasma, distribution into tissues and then back into plasma, where the drug can then be eliminated from the body either by metabolism or excretion of parent drug and/or metabolites. Many factors influence each of these four drug movements (ADME) and thus the time course of plasma drug concentrations after a dose is administered by any route. Understanding these factors, in turn, is important to individualizing drug therapy for the patient, because dosing regimens are modified to adjust for physiologic (eg, species, breed, gender, age), pharmacologic (eg, drug-drug or drug-diet interactions), and pathologic (eg, renal, hepatic, or cardiac disease) influences on drug disposition. Pharmacokinetics is the science that mathematically describes the time course of plasma drug concentrations after administration of a dose, ie, the result of ADME on plasma drug concentrations.

Passage of Drugs Across Cellular Membranes

Each of the drug movements generally relies on the drug passing through cell membranes (transcellular). Membrane barriers may be composed of several layers of cells (eg, skin, vagina, cornea, placenta) or a single layer of cells (eg, enterocytes, renal tubular epithelial cells), or they may consist only of a boundary less than one cell in thickness (eg, hepatic sinusoids). Multilayered tissues each may present different types of barriers, eg, skin is protected by the dense stratum corneum, which is absent in mucous membranes. Not all drugs must pass through cell membranes; paracellular movement between cells increasingly is an important movement for some drugs, eg, in the GI tract.

Drugs and other molecules cross cellular membranes by several processes. Methods by which drugs move include bulk flow (eg, movement with blood, glomerular filtration), passive diffusion, carrier-mediated transport (ie, active or facilitated transport), and pinocytosis. Of these, passive diffusion is most important for movement of drug molecules and other xenobiotics (foreign chemicals), as well as many endogenous compounds.

The rate at which a drug passively diffuses through membranes is influenced by several factors, the most important of which is the concentration gradient of diffusible (eg, dissolved) drug across the membrane. However, other host and drug factors influence the rate and extent of passive diffusion. Host factors that increase diffusion include permeability and surface area of the membrane; thickness of the membrane negatively impacts diffusion. Drug characteristics that influence diffusion include molecular weight, lipophilicity, and degree of ionization. Most drugs are "small molecules" (<900 daltons), but diffusibility is more likely to occur for drugs <500 daltons. Drugs must be sufficiently lipid soluble (lipophilic) to pass through some level of cell membrane lipid bilayer to reach most drug receptors. The lipid-to-water partition coefficient describes the distribution (ratio) of a drug (concentration) in a lipid compared with water media. The distribution coefficient also takes into account ionization.

Many drugs are weak organic acids or bases. At physiologic pH, they tend to be partially ionized (dissociated) and partially nonionized (undissociated); the ratio of the respective forms depends on the dissociation constant (pKa) of the drug, ie, the pH at which the drug is present in equal concentration in ionized and nonionized forms, and the pH of the solution in which the drug is dissolved. Only nonionized fraction diffuses through lipid membranes. Distribution across any membrane of a drug with any given pKa reflects the degree of ionization and thus environmental pH on each side of the membrane. The Henderson Hasselbach equation predicts the ratio of ionized vs nonionized drug. In general, weak acids are nonionized in acidic compared with alkaline environments, and weak bases are nonionized in alkaline compared with acidic environments. The more similar the environmental pH is to that of the pKa of a weak acid or base, the more nonionized is the drug and the more likely it will diffuse. As long as the ratio of nonionized to ionized drug is ≥0.01, the drug is considered diffusible.

Not all drugs must pass through cell membranes to reach their receptor. Aqueous pores in lipoproteinaceous biologic membranes offer a means of xenobiotic movement through the membrane for predominantly aqueous soluble drugs. Lipid-insoluble (water-soluble) compounds pass easily through these pores and to a lesser degree directly through the membrane. A hydrostatic or osmotic pressure difference across a membrane facilitates movement by promoting water flow through the aqueous pores. Bulk fluid movement carries or “drags” solute molecules through the pores as long as the solute molecules are smaller than the aqueous channels.

Several specialized transfer processes account for the passage of certain organic ions and other large lipid-insoluble substances across biologic membranes. Active transport, facilitated diffusion, and exchange diffusion are three distinct types of carrier-mediated systems used to move specific substances across cellular membranes. The highly selective carrier-mediated systems are principally used for transporting nutrients and natural substrates across biologic membranes. Among the mechanisms of active transport are transport proteins that move compounds, including drugs, into or out of cells. Transport proteins are located at portals of entry (eg, enterocytes of the GI tract or sinusoidal hepatic cells) or “sanctuary” tissues (eg, brain, CSF, placenta, prostate, eyes, or testicles), where they attempt to ensure that xenobiotics do not enter the protected tissue. As such, transport proteins are able to influence each drug movement (absorption, distribution, metabolism, and excretion). The most well known of the transport proteins is the ATP-binding cassette superfamily of efflux transporters, which includes P-glycoprotein, the multidrug resistance protein. Substrates for P-glycoprotein include both xenobiotics and dietary components. Additional transport proteins carry cations, anions, or organic compounds. Competition for transport increases oral absorption or distribution of one of the competing molecules.

Pinocytosis is an important transport process in mammalian cells, particularly intestinal epithelial cells and renal tubular cells. Drugs that exist in solution as molecular aggregates have large molecular masses themselves or that are bound to macromolecules may be transferred across membranes by pinocytosis.

Drug Absorption

Absorption from the GI Tract:

Many factors influence orally administered drugs. Before absorption, orally administered drugs must disintegrate and then dissolve; dissolution often is the rate-limiting factor in oral drug absorption. Drugs may be formulated by manufacturers to result in extended (occurring throughout the GI tract) or delayed absorption. Often, release kinetics of these drugs limit extrapolation of dosing regimens from one species to another. Once an orally administered drug has dissolved, multiple factors influence its absorption. Drug characteristics include molecular size, lipophilicity, and drug pKa. Drug pKa is particularly important in the GI tract, because environmental pH is markedly variable among the different regions or compartments. Host factors (in addition to environmental pH) determining oral absorption include epithelial permeability, GI motility, surface area (being greatest in the small intestine, which is the major site of drug absorption), transport and metabolizing proteins, and GI blood (which maintains the concentration gradient) and lymphatic flow. Epithelial permeability is influenced by disease. Additionally, in those species in which colostrum absorption is important, epithelial permeability is much greater. GI motility is important because it influences mixing of luminal contents, which is necessary for dissolved drug to come into contact with absorptive surfaces. Gastric motility determines gastric emptying, which in turn influences the rate of drug absorption. Changes in GI blood flow have minimal impact on drug absorption, because although GI blood flow maintains the concentration gradient necessary for passive diffusion, it is rarely the rate-limiting factor. Both efflux transport proteins (eg, P-glycoprotein) and drug-metabolizing enzymes located in the GI epithelium can markedly decrease drug absorption, contributing to a "first-pass effect." These proteins are subject to clinically relevant drug interactions and are likely to differ among physiologic influences (eg, species, gender, age). A drug entering the portal circulation will be exposed to hepatocytes before reaching systemic circulation. If a large proportion of the drug (>75%) is removed or extracted as it passes through the liver, the oral bioavailability of the drug will be markedly reduced, also resulting in a "first-pass effect." For such drugs, the oral dose is proportionately higher than the parenteral dose. Food can markedly alter oral absorption of drugs by either diluting it, or more importantly, binding to it so that it is not absorbed.

Absorption from Topical Administration:

Drugs may be absorbed through the skin after topical application; however, the stratum corneum presents an effective barrier to transdermal movement of most drugs into circulation. As such, many drugs are absorbed after paracellular rather than transcellular movement. Intact skin allows the passage of small lipophilic substances but efficiently retards the diffusion of water-soluble molecules in most cases. Lipid-insoluble drugs generally penetrate the skin slowly compared with their rates of absorption through other body membranes. Absorption of drugs through the skin may be enhanced by heat, moisture, or disruption of the stratum corneum. Occlusive dressings increase heat and moisture; transdermal patches also disrupt the stratum corneum. Smaller molecules are more conducive to transdermal drug delivery. Different transdermal systems have been developed with the intent of systemic drug delivery. Certain solvents (eg, dimethyl sulfoxide [DMSO]) may facilitate the penetration of drugs through the skin. Damaged, inflamed, or hyperemic skin allows many drugs to penetrate the dermal barrier much more readily. For example, drugs administered transdermally as pluronic lecithin or other gels presumably penetrate the stratum corneum because it is disrupted, becoming more permeable. The same principles that govern the absorption of drugs through the skin also apply to the application of topical preparations on epithelial surfaces. In contrast to skin, mucosal epithelium has no stratum corneum, facilitating drug absorption. An advantage of the buccal mucosa is that a drug avoids first-pass metabolism.

Absorption from Tracheobronchial Surfaces and Alveoli:

Because volatile and gaseous anesthetics have relatively high lipid-to-water partition coefficients and generally are rather small molecules, they diffuse practically instantaneously into the blood in the alveolar capillaries. In contrast, for drugs administered as aerosols, particles containing drugs can be deposited on the mucosal surface of the bronchi or bronchioles, or even in the alveoli, with the site influenced by particle size and breathing rate and depth. Whether or not the drug is absorbed from these sites depends on the characteristics previously described.

Absorption from Injection Delivery Sites:

After nonintravenous injection, diffusible drug molecules traverse the capillary wall by a combination of diffusion and filtration. Diffusion is the predominant mode of transfer for lipid-soluble molecules, small lipid-insoluble molecules, and ions. Because most capillaries are fenestrated, all drugs, whether lipid-soluble or not, cross the capillary wall at rates that are extremely rapid compared with their rates across other body membranes. In fact, the movement of most drug molecules in various tissues is limited only by the rate of blood flow rather than by the capillary wall. However, endothelial cells of sanctuaries, such as the blood-brain or CSF barrier, retina, and testicles, have tight intercellular junctions, thus restricting movement of drugs.

Aqueous solutions of drugs are usually absorbed from an IM injection site within 10–30 min, provided blood flow is unimpaired. Faster or slower absorption is possible, depending on the concentration and lipid solubility of the drug, vascularity (including number of vessels and state of vasoconstriction), the volume of injection, the osmolality of the solution, and other pharmaceutical factors. Substances with molecular weights >20,000 daltons are principally taken up into the lymphatics.

Absorption of drugs from subcutaneous tissues is influenced by the same factors that determine the rate of absorption from IM sites. Some drugs are absorbed as rapidly from subcutaneous tissues as from muscle, although absorption from injection sites in subcutaneous fat is always significantly delayed.

Increasing blood supply to the injection site by heating, massage, or exercise hastens the rate of dissemination and absorption.

The rate of absorption of an injected drug may be prolonged in a number of ways, including immobilization of the site, local cooling, a tourniquet, incorporation of a vasoconstrictor, an oil base, and implant pellets and insoluble “depot” preparations. Among these depot preparations are drugs that are converted to less soluble esters, which must be released by esterases (eg, procaine and benzathine esters of penicillin or acetate esters of steroids) or less soluble complexes (eg, protamine zinc insulin), or that are administered as insoluble microcrystalline suspensions (eg, methylprednisolone acetate).

Bioavailability

Bioavailability refers to the extent to which a drug is absorbed into the body and thus is available to act on its intended target site. A drug is considered 100% bioavailable (F=1) when given intravenously (although pulmonary metabolism may make this not entirely true). Bioavailability of a particular route or formulation is the ratio of the area under the plasma drug concentration versus time curve (AUC) of the drug when the drug is given via that route or as that preparation to the AUC when the drug is given intravenously at the same dosage (in mg/kg):

F = AUCnon-IV/AUCIV

The equation must be adjusted for dosage when appropriate:

F = (AUCnon-IV) × (doseIV)/(AUCIV) × (dosenon-IV)

Two products are considered bioequivalent if they result in the same rate and extent of absorption. Rate of absorption is reflected as the maximum plasma drug concentration (Cmax) and the time (Tmax) that Cmax occurs. Thus, two drugs are bioequivalent if their AUC, Cmax, and Tmax do not significantly differ. Two different preparations or routes of administration may be equally bioavailable but not bioequivalent. Generic drugs must be demonstrated to be bioequivalent.

Once a drug reaches the systemic circulation, all other drug movements (distribution, metabolism, and excretion) will be the same regardless of the route or preparation. However, in some instances, absorption may be so slow (eg, delayed or extended-release formulation, absorption impacted by food) that it limits the rate at which the drug is eliminated (metabolized and/or excreted) from the body.

Drug Distribution

After absorption into the bloodstream, drugs are disseminated to all parts of the body. Occasionally, the drug molecule may be so large (>65,000 daltons) or so highly bound to plasma proteins that it remains in the intravascular space after IV administration. Compounds that permeate freely through cell membranes become distributed, in time, throughout the body water to both extracellular and intracellular fluids, with the extent depending on drug chemistry. Substances that pass readily through and between capillary endothelial cells, but do not penetrate other cell membranes, are distributed into the extracellular fluid space. Drugs may also undergo redistribution in the body after initial high levels are achieved in tissues that have a rich vascular supply, eg, the brain. As the plasma concentration falls, the drug readily diffuses back into the circulation to be quickly redistributed to other tissues with high blood-flow rates, such as the muscles; over time, the drug also becomes deposited in lipid-rich tissues with poor blood supplies, such as the fat depots. Most drugs are not distributed equally throughout the body but tend to accumulate in certain specific tissues or fluids. The general principles that govern the passage and distribution of drugs across cellular membranes (see Passage of Drugs Across Cellular Membranes) are applicable to drug distribution. Basic drugs tend to accumulate in tissues and fluids with pH values lower than the pKa of the drug; conversely, acidic drugs concentrate in regions of higher pH, provided the free drug is sufficiently lipid soluble to penetrate the membranes that separate the compartments. Even small differences in pH across boundary membranes, such as those that exist between plasma (pH 7.4) and other tissues such as CSF (pH 7.3), milk (pH 6.5–6.8), renal tubular fluid (pH 5–8), and inflamed tissue (pH 6–7) can lead to unequal distribution of drugs, referred to as "ion-trapping." Only freely diffusible and unbound drug molecules are generally able to pass from one compartment to another. However, some drugs are transported by carrier-mediated systems across certain cellular membranes, which leads to higher concentrations on one side than the other. Examples of such nonspecific transport mechanisms are found in renal tubular epithelial cells, hepatocytes, and the choroid plexus. Among the transport proteins, genetic differences in P-glycoprotein profoundly impact drug movement, particularly at portals of xenobiotic entry or sanctuaries.

Passive diffusion of drugs from capillaries to tissues may be limited by binding to plasma proteins. The most important is albumin, although the globulins and, especially, α-1 acid glycoprotein (for bases) may also play a significant role. In general, protein binding is considered clinically relevant if ≥80%. For such drugs, factors influencing binding can impact drug disposition. These include plasma pH, concentration of plasma proteins, concentration of the drug, or the presence of a competing agent with a greater affinity for the limited number of binding sites. For example, a potentially toxic compound (such as most NSAIDs) may be 98% bound, but if for any reason it becomes only 96% bound, then the concentration of the free active drug that becomes available in the plasma is doubled, with potentially harmful consequences. The concentration of a drug administered in overdose may exceed the binding capacity of the plasma protein and lead to an excess of free drug, which can diffuse into various target tissues and produce exaggerated effects. Other reasons the fraction of unbound drug might increase include hypoalbuminemia and competition with other highly protein-bound drugs. The degree of protein binding of a drug cannot be extrapolated among the species, but in most species, NSAIDs, antifungal imidazoles, and doxycycline are examples of highly protein-bound drugs. More rapid clearance of the now unbound drug may mitigate the impact of higher drug concentrations.

Dissociation of a drug from plasma proteins also influences elimination from the body in that those drugs more tightly bound tend to have much longer elimination half-lives, because they are released gradually from the plasma protein reservoir (eg, cefovecin or long-acting sulfonamides).

Most unbound drugs distribute easily from capillaries to extracellular fluid. However, only the more lipid-soluble drugs can distribute to all tissues because of the presence of physiologic barriers presented by "sanctuaries" (eg, blood-brain, placental, and mammary barriers). For the CNS, drugs may gain access through either the capillary circulation (blood-brain barrier) or the CSF (also a blood barrier). Drugs penetrate into the cortex more rapidly than into white matter, probably because of the greater delivery rate of drug via the bloodstream to the tissue.

The pharmacologic factors and consequences of the diverse rates of entry of different drugs into the CNS are clinically relevant in that water-soluble, ionized drugs are less likely to enter the CNS, whereas drugs with low ionization, low plasma-protein binding, and a fairly high lipid-water partition coefficient penetrate more rapidly. Inflammation, presented by for example meningoencephalitis, can substantially alter the permeability of the blood-brain barrier. In general, direct injection into the CSF is undesirable because of the risk of unexpected effects.

In pregnant animals, the degree of placentation may determine the extent of a placental barrier. Nutrients such as glucose, amino acids, minerals, and even some vitamins are actively transported across the placenta. The passage of drugs across the placenta is largely by lipid diffusion, and the factors discussed above play a role. The distribution of drugs within the fetus follows essentially the same pattern as in the adult, with some differences with respect to the volumes of drug distribution, plasma-protein binding, blood circulation, and greater permeability of interceding membranous barriers. Drugs that are potentially teratogenic should be avoided, particularly in early gestation.

The mammary gland epithelium, like other biologic membranes, acts as a lipid barrier, and many drugs readily diffuse from the plasma into milk. The pH of normal milk varies, being 6.5–6.8 in goats and cows. As such, weak bases tend to accumulate in milk. Drugs delivered by intramammary infusion can diffuse into plasma to a greater or lesser degree by the same processes noted earlier.

Once a drug is distributed into tissues, binding to macromolecules such as protein components of cells or fluids, dissolution in adipose tissue, formation of nondiffusible complexes in tissues such as bone, incorporation into specific storage granules, or binding to selective sites in tissues all impede movement of drugs back into plasma and account for differences in the cellular and organ distribution of particular drugs.

Drug Metabolism

Drugs that are lipid soluble will be passively reabsorbed as urine concentrates in the kidney unless they are converted by enzymatic processes to water-soluble drugs. This is accomplished by drug metabolism. Metabolism and subsequent excretion of drugs together comprise drug “elimination” from the body. Most drug metabolism occurs in the smooth endoplasmic reticulum of the liver. Metabolism generally consists of two phases: Phase I induces a chemical change (most frequently oxidation, but also reduction) that renders the drug more conducive to phase II. Phase II is a conjugative or synthetic addition of a large, polar molecule that renders the drug water soluble and amenable to renal excretion.

Four possible sequelae follow phase I metabolism: 1) inactivation (eg, most NSAIDs); 2) activation from a "pro-drug" to the active form of the drug (eg, enalapril to enalaprilat); 3) modification of activity, ie, formation of active metabolites that may be characterized by activity greater than (eg, tramadol), less than (eg, diazepam), or equal to that of the parent compound; and 4) formation of toxic metabolites, which is generally due to direct cell damage (eg, acetaminophen). In some instances the toxic metabolite acts as an antigen, causing immune-mediated toxicity (eg, sulfonamides). Because phase II drug metabolism almost exclusively inactivates drugs (the notable exception being some acetylated and methylated drugs), it often protects the organ of metabolism from drug-induced toxicity. This is particularly true with the addition of glutathione, which scavenges oxygen radicals; in the face of drug toxicity, N-acetylcysteine will increase intracellular glutathione. Multiple isoforms of phase II drug-metabolizing enzymes exist. Glucuronide (the addition of which is catalyzed by glucuronide transferase) is the most common phase II reaction; cats are deficient in some, but not all, glucuronyl transferases. Other important phase II enzymes include sulfation (deficient in swine), acetylation (deficient in dogs), and methylation. Amino acid conjugations are particularly important in avian species.

Phase I drug metabolism is largely, but not exclusively, accomplished by heme-containing enzymes referred to as cytochrome P450 (CYP450). More than 20 superfamilies have been identified, with some being specific for some drug or drug classes but others characterized by broad substrate specificity. Among the major superfamilies are CYP3A, which in people has been demonstrated to be responsible for the larger proportion of drug metabolism. Others important to drug metabolism are CYP2C and CYP2D. CYP enzymes are responsible for synthesis (eg, adrenal steroids, fatty acids) and metabolism of many endogenous compounds.

Drug metabolism has largely been considered to be negligible in early life, with neonates being less able to eliminate lipid-soluble drugs than adults; dosing intervals should be prolonged in such instances. However, evidence is emerging that some pediatric animals may have increased rather than decreased metabolic capacity for some drugs compared with adults. In those instances in which metabolic capacity has been demonstrated to be less, postnatal development in the liver appears to be biphasic, consisting of a rapid and nearly linear increase in activity during the first 3–4 wk, followed by slower development up to the tenth week postpartum. In older animals, decreases in hepatic mass, hepatic blood flow, and drug-metabolizing enzyme activity should lead to longer dosing intervals, and for drugs characterized by first-pass metabolism, to lower oral doses.

Many disease states impair the normal activity of the hepatic drug-metabolizing enzyme systems, which in turn decreases clearance and thus prolongs the half-lives of many drugs. Hepatotoxicity, acute hepatitis, or other extensive liver lesions invariably depress enzyme activity. Evidence of decreased plasma albumin as a result of hepatic disease generally indicates that hepatic drug metabolism will likewise be decreased. Hypothyroidism tends to decrease, and hyperthyroidism increase drug-metabolizing enzyme activity.

Pharmacogenomics refers to the study of the genetic basis for differential response to drugs. Differences in the duration of action of drugs in various species frequently can be attributed to differences in their rates of biotransformation. Species variations in drug metabolism are common. CYP450 3A4 is responsible for the broadest substrate activity in people, but this may not be true in animals and certainly may vary among species.

Differences in content and activity of CYP enzymes among ages, genders, and species are likely to play a role in differences to response to drugs. Polymorphisms among the breeds can result in "poor" versus "efficient" metabolizers, with the former predisposed to drug toxicity because of decreased metabolism. Such variants for certain enzymes have been described in people as being responsible for potentially lethal differences in drug metabolism.

Several other factors impact the rate and extent of drug metabolism. Drug interactions may reflect induction (eg, phenobarbital, rifampin, griseofulvin) or inhibition (eg, chloramphenicol, cimetidine, imidazole antifungals) of CYP enzymes, with the impact varying among isoenzymes and the sequelae of drug metabolism. Nutritional state and disease (especially hepatic disease) can also impact drug metabolism. The liver is not the only site of CYP450 activity, with sanctuaries and portals of entry being examples of sites where CYP activity can alter several aspects of ADME.

In addition to differences in CYP450 enzymes, differential handling of enantiomers is increasingly recognized among species. Enantiomers are mirror images of drug molecules that result when groups of atoms rotate around a center or “chiral” carbon. Generally, such compounds are sold as racemic mixtures (50:50 of each isomer); however, the body frequently handles each stereoisomer differentially, with differences also being seen among species. Many cardiac drugs and NSAIDs exist as racemic mixtures of enantiomers. This must be remembered when either dosages or withdrawal times are extrapolated from one species to another. However, some drugs are sold only as one isomer or the other, with the name often reflecting as such (eg, levetiracetam, dexmedetomidine, esomeprazole). Species differences have been better documented for phase II metabolism. Among the more important phase II reactions and the species in which the reactions are deficient are glucuronidation (cats), glutathione transferase (important for scavenging potentially toxic metabolites), sulfation (swine), and acetylation (dogs).

Drug Excretion

The body can clear itself of drugs either by metabolism or excretion. Excretion irreversibly removes drugs or metabolites 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 and contributes to milk discard times.

Renal excretion of foreign compounds is accomplished either by glomerular filtration, passive diffusion into and out (eg, resorption) of the tubular lumen, and carrier-mediated secretion (eg, active transport or facilitated diffusion).

Among the more important factors determining renal excretion is renal blood flow, which in turn is influenced by cardiac output. Glomerular filtration in particular, but also carrier-mediated transport, is influenced by changes in cardiac output. Drugs that impact renal blood flow (eg, angiotensin converting-enzyme inhibitors) can also impact renal clearance.

Only unbound molecules <66,000 daltons are readily filtered through the glomerular membranes into the tubular lumen. Most active tubular secretion of drugs into tubules (renal exertion) occurs in the proximal convoluted tubule. Binding to plasma proteins usually does not hinder tubular excretion of drugs. Transport proteins exist for weak acids (anions), bases (cations), or organic compounds. Most (passive) reabsorption of nonionized, lipid-soluble drugs occurs as urine is concentrated in the distal and collecting tubules. Acidification or alkalinization of the urine may alter the rate of excretion of some drugs because of ion trapping in the tubular fluid.

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.

Among the more important factors impacting renal excretion is renal or cardiac disease. Decreased renal blood flow will result in a proportional decrease in renal excretion. However, renal disease may also be accompanied by changes in the metabolic capacity of the kidneys and production of toxins that will compete with drug for protein-binding sites. Changes in acid-base balance may also influence urine pH.

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. Generally, biliary excretion occurs for drugs with molecular weights that exceed 600 daltons. Biliary excretion is a relatively slow process. Further, many drugs excreted in bile as glucuronide conjugates may become unconjugated by intestinal microflora. Released drug can be reabsorbed into the systemic circulation, resulting in "enterohepatic circulation." Such recirculation often accounts 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 other routes of excretion are of lesser clinical importance. Many drugs are excreted in the feces either because of limited oral absorption or diffusion directly into the GI tract. The ruminoreticulum can act as a drug reservoir because of ion trapping or can remove a drug because of microbial metabolism. The tracheobronchial tree also may be a potential avenue of excretion, as is alveolar elimination of inhalant anesthetics. 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, although such drugs are likely to enter the GI tract.