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CHAPTER OBJECTIVES

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  • Describe the main routes of drug elimination from the body.

  • Understand the importance of the role of clearance as a PK parameter.

  • Define clearance and its relationship to a corresponding half-life and a volume of distribution.

  • Differentiate between clearance and renal clearance.

  • Describe the processes for renal drug excretion and explain which renal excretion process predominates in the kidney for a specific drug, given its renal clearance.

  • Describe the renal clearance model based on renal blood flow, glomerular filtration, and drug reabsorption.

  • Describe organ drug clearance in terms of blood flow and extraction.

  • Calculate clearance using different methods including the physiological, noncompartmental, and compartmental approaches.

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DRUG ELIMINATION

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Drugs are removed from the body by various elimination processes. Drug elimination refers to the irreversible removal of drug from the body by all routes of elimination. The declining plasma drug concentration observed after systemic drug absorption shows that the drug is being eliminated from the body but does not necessarily differentiate between distribution and elimination, and does not indicate which elimination processes are involved.

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Drug elimination is usually divided into two major components: excretion and biotransformation. Drug excretion is the removal of the intact drug. Nonvolatile and polar drugs are excreted mainly by renal excretion, a process in which the drug passes through the kidney to the bladder and ultimately into the urine. Other pathways for drug excretion may include the excretion of drug into bile, sweat, saliva, milk (via lactation), or other body fluids. Volatile drugs, such as gaseous anesthetics, alcohol, or drugs with high volatility, are excreted via the lungs into expired air.

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Biotransformation or drug metabolism is the process by which the drug is chemically converted in the body to a metabolite. Biotransformation is usually an enzymatic process. A few drugs may also be changed chemically1 by a nonenzymatic process (eg, ester hydrolysis). The enzymes involved in the biotransformation of drugs are located mainly in the liver (see Chapter 12). Other tissues such as kidney, lung, small intestine, and skin also contain biotransformation enzymes.

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Drug elimination in the body involves many complex rate processes. Although organ systems have specific functions, the tissues within the organs are not structurally homogeneous, and elimination processes may vary in each organ. In Chapter 4, drug elimination was modeled by an overall first-order elimination rate process. In this chapter, drug elimination is described in terms of clearance from a hypothetical well-stirred compartment containing uniform drug distribution. The term clearance describes the process of drug elimination from the body or from a single organ without identifying the individual processes involved. Clearance may be defined as the volume of fluid removed of the drug from the body per unit of time. The units for clearance are sometimes in milliliters per minute (mL/min) but most often reported in liters per hour (L/h). The volume concept is simple and convenient, ...

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