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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 because 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. The concept of drug clearance is of great clinical significance. |
| 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. |
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Steady State Plasma Concentration (Repeated Administration or Constant IV Infusion): |
| 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. |
| 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. The size of the dose and the route of administration have little effect. 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. 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. |
| 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. |
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