THE MERCK VETERINARY MANUAL
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Pharmacokinetics

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The pharmacokinetic characteristics of a particular drug (rates of absorption, distribution, biotransformation, and excretion) determine its concentration in the plasma. Because the intensity of the tissue response is usually determined by the concentration of the drug in the direct environment of the receptors, a drug's concentration in plasma is generally assumed to be correlated with the time course of its action. Dosage regimens are derived from pharmacokinetic studies in normal animals but often require modification in diseased, young, old, obese, thin, or pregnant animals. A large number of pharmacokinetic measures can be determined from time-course studies of drug concentrations in plasma, but only the more clinically useful features and values are emphasized here.

Drug Concentration in Blood

Drug concentrations in the blood can be determined and graphed against time. In most instances, the time course of a drug's concentration in the plasma correlates well with the onset, intensity, and duration of the pharmacologic effect. Thus, the measurement of sequential plasma concentration of drugs after their administration is used to establish dosage regimens that are likely to produce the desired therapeutic levels for appropriate periods of time, without the risk of drug failure or toxicity.

From the single-dose concentration curves (extravascular and intravascular), a number of pharmacokinetic parameters can be calculated. These include the transfer rate constants between central and peripheral compartments; the elimination rate constant (Kel) for disappearance of drug from the central compartment; and the elimination half-life (t½), which has important clinical significance when determining dosing interval.

When a drug is administered by an extravascular route, it usually appears in the plasma within a short time, and its concentration rises steadily until it peaks. Once absorbed into the circulation, it is subjected simultaneously to distribution, biotransformation, and excretion. During the initial period, the rate of absorption and distribution exceeds the rate of elimination. The peak plasma concentration is reached when absorption and elimination rates are equal. Thereafter, the elimination rate exceeds the rate of absorption because less drug remains available at the site of administration, and plasma drug levels begin to fall.

The term “bioavailability” is used to express the rate and extent of absorption of a drug, usually from the GI tract after administration PO. Bioavailability is determined by administering equal doses of a drug by the IV (absorption effectively 100%) and PO routes and then comparing the areas under the 2 curves. Bioavailability is expressed as a percentage. The same principles can be applied to calculation of the bioavailability of drugs administered by other routes.

When a drug is administered by rapid IV injection, the maximum concentration in the blood is reached almost at once and immediately begins to fall. The profile of this decline can be determined by monitoring blood levels at periodic intervals and then plotting these concentrations against time.

Apparent Volume of Distribution

The pharmacokinetic measure used to indicate the pattern of distribution of a drug in plasma and in the different tissues, as well as the size of the compartment into which a drug would seem to have distributed in relation to its concentration in plasma, is known as the apparent volume of distribution (Vd). Simplistically, it is the volume of tissue that dilutes the drug once distribution is complete. It is usually reported as liters per kilogram (L/kg). The apparent Vd for a drug is determined by its degree of water or lipid solubility, the extent of plasma- and tissue-protein binding, and the perfusion of tissues. Drugs that tend to maintain high concentrations in the plasma because of low lipid solubility, extensive binding to plasma proteins, and diminished tissue binding have a low Vd, similar to plasma volume. Drugs whose distribution is limited to extracellular fluid generally are characterized by a Vd approximates 30% of the body weight (0.3 L/kg). Drugs that are able to penetrate cell membranes are distributed to total body water and generally have a Vd that is at least 60% of the body weight, or 0.6 L/kg. Binding or trapping of the drug in a peripheral site will cause the drug to leave circulation, resulting in a large Vd that may exceed the weight of the animal. The value of Vd is characteristic for a drug and is usually constant over a wide dose range for a given species. However, a number of clinically significant factors can influence the Vd including age; functional status of the kidneys, liver, and heart; fluid accumulations; concentration of plasma proteins; acid-base status; inflammatory processes or necrosis; and any other causes for alteration in the degree of plasma-protein binding. Vd is used to determine dose. A dose necessary to achieve desired plasma concentration can be calculated from the formula D = C × Vd × body wt (in kg), in which D is the dose and C is the required plasma concentration for a given drug.

Drug Clearance (Elimination)

Once a drug is absorbed and distributed among the tissues and body fluids, it is then eliminated, or cleared, mainly by the liver and kidneys. Consequently, the plasma concentration of a drug decreases steadily, although at different rates for various drugs in different species. After a single dose, only ∼3% of a given dose remains in the body after 5 half-lives; 96.87% has been cleared by this time. Drug clearance (Cl) is defined as the volume of plasma that would contain the amount of drug excreted per minute or, alternatively, the volume of plasma that would have to lose all of the drug that it contains within a unit of time (usually 1 min) to account for an observed rate of drug elimination. Thus, clearance expresses the rate or efficiency of drug removal from the plasma but not the amount of drug eliminated.

Renal clearance is defined as the volume of plasma that is totally cleared of a drug in 1 min during passage through the kidneys. The renal clearance of drugs depends on urine pH, extent of plasma-protein binding, and renal plasma flow. These factors may vary from animal to animal as well as among species, because of differences in diet, environmental temperature, physical activity, disease, and concomitant use of certain drugs. For drugs that are excreted primarily by glomerular filtration, the animal's creatinine clearance may serve as an indicator of drug clearance because creatinine undergoes complete glomerular filtration while being subjected to minimal tubular reabsorption. Consequently, creatinine clearance rate can be used for adjusting dosage schedules of some drugs in animals with impaired renal function.

Hepatic clearance is defined as the volume of plasma that is totally cleared of drug in 1 min during passage through the liver. Most drugs, except highly hydrophilic compounds, are cleared from the plasma mainly by biotransformation in the liver, although biliary excretion can also contribute to the hepatic clearance of a drug. The main factors that determine hepatic clearance include hepatic blood flow (delivery of drug to the liver), uptake of the unbound drug by the hepatocytes from the blood, metabolic transformation of the drug by microsomal or other enzyme systems, and rate of biliary secretion.

Some drugs undergo substantial removal from the portal circulation by the liver after administration PO. This “first-pass” effect can significantly reduce the amount of parent drug that reaches the systemic circulation. A number of factors can modify the magnitude of the first-pass effect for a particular drug. Hepatic clearance can be impaired by liver disease, biliary stasis, decreased hepatic blood flow, and drugs that inhibit microsomal enzyme systems. Microsomal enzyme inducers often increase hepatic clearance of a concurrently administered drug. There is no reliable liver function test to assess the impediment of hepatic clearance of drugs (as creatinine clearance does for the kidneys). The dose rates for drugs used in animals with liver disease must be adjusted on clinical judgment alone.

In some cases, the desired therapeutic effect of a drug is produced with a single dose. However, to achieve a satisfactory response, it is frequently necessary to maintain drug concentrations in the therapeutic range for a longer time. Rather than administering large doses, which could be potentially toxic, repeated safe doses at regular intervals or continuous IV delivery are generally necessary. The rate of administration depends on the amount of fluctuation in drug concentration that can occur during a dosing interval and the drug elimination half-life.

When a drug is infused IV, the plasma concentration continues to rise until elimination equals the rate of delivery into the body. Regardless of the drug, 50% of the plateau concentration is attained in 1 half-life of the drug; for 2, 3, and 4 half-lives, 75%, 87.6%, and 93.6% of the plateau concentration are reached, respectively. For practical purposes, steady state is achieved by 3–5 half-lives. The time required to reach steady state depends only on the drug's half-life. The shorter the half-life, the more rapidly steady state is reached. For drugs with very short half-lives, steady state or a state of equilibrium does not occur unless the interval is likewise very short. The size of the dose and the route of administration have no effect on the time to steady state because it is a function of half-life, which in turn, is determined by volume of distribution (directly proportional) and clearance (inversely proportional). Consequently, whether a drug is delivered by constant or intermittent IV injection, by other parenteral routes (provided there is no pharmaceutical manipulation to delay absorption), or PO, a steady state concentration is reached after at least 5 half-lives. The magnitude of drug concentrations at steady state compared with the first dose is determined by the relationship between dosing interval and the half-life. For drugs with a long half-life compared with the dosing interval, the drug will markedly accumulate, and chronic dosing is designed to achieve the therapeutic range at steady state. For drugs with a short half-life compared with the dosing interval, most of the drug is eliminated between doses, with little accumulation.

A drug normally requires some time to reach steady state. When some haste is necessary, plasma levels may be achieved more rapidly by the administration of a loading dose or doses. This entails the administration of a single large dose or smaller doses at frequent intervals to bring the concentration in plasma quickly to the level desired during the steady state. The loading dose required to achieve the plasma levels present at steady state can be determined from the fraction of drug eliminated during the dosing interval and the maintenance dose. It is important to note that the drug is not at steady state, but only at steady state concentrations. Steady state requires the administration of the same dose for 3–5 drug elimination half-lives. If the maintenance dose given after the loading dose does not maintain what the loading dose achieved, drug concentrations will slowly decline or increase until a new steady state is reached 3–5 elimination half-lives after maintenance dosing begins.

An appropriate dosing interval for most drugs depends on the distance between the maximum and the minimum target drug concentration (ie, therapeutic range). Shorter dosing intervals compared with half-life increase the risk of drug-induced toxicity because of increased blood levels. Prolonged dosing intervals diminish the drug's efficacy because of decreased blood levels. Often, however, dosing intervals equal to the half-lives are impractical for drugs with short half-lives. In most cases, either high doses of a relatively nontoxic drug are given to attain therapeutic concentrations for a sufficient time period, or potentially harmful drugs are administered by careful IV infusion. Another approach is to use dosage formulations or devices that allow for a more gradual release of the active principle into the systemic circulation.

Last full review/revision March 2012 by Dawn Merton Boothe, DVM, PhD, DACVIM, DACVCP; Philip T. Reeves, BVSc (Hons), PhD, FANZCVS

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