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18.1 GENERAL PRINCIPLES OF PHARMACOLOGY

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In this chapter, general principles of pharmacology relevant to anticancer drugs are presented. The specific properties of the most important anticancer drugs in clinical use are reviewed, with emphasis on their structure, mechanism of action, pharmacokinetics, and toxicity. In systemic cancer therapy, it is common to combine several drugs. Drugs in such combinations generally have different mechanisms of action, and different toxicity profiles, so that each drug can be administered at close to its maximally tolerated dose. Combination therapy may overcome tumor resistance to an individual drug, and is generally more efficacious than a single drug. It is also common to combine surgery, radiation, and chemotherapy in treatment. Adjuvant chemotherapy and/or radiation are usually given after the definitive management of the primary cancer through surgery. The purpose of adjuvant chemotherapy is to eradicate micrometastatic disease, and reduce the risk of tumor recurrence. Adjuvant chemotherapy is given for a defined period of time, generally 4 to 6 months. Neoadjuvant chemotherapy refers to chemotherapy given before the definitive management of the primary cancer, and is given to reduce the size of the primary tumor for better cosmetic and functional outcomes.

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18.1.1 Pharmacokinetics and Pharmacodynamics

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Pharmacokinetics is the study of the time course of drug and metabolite levels in different body fluids and tissues, including absorption, distribution, metabolism, and elimination. The study of the relationship between drug effect and its concentration is known as pharmacodynamics. Alterations in pharmacokinetic properties of a drug may result in different drug concentrations over time at tissue levels. Understanding the pharmacodynamics of the drug can help to account for subsequent differences in drug effect or response.

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Although most anticancer drugs are administered intravenously and drug absorption is not a therapeutic concern, many newer agents are given orally. Oral drug administration is convenient for patients, but it requires patient compliance and depends on efficient absorption from the gastrointestinal tract. For an orally administered drug, only a proportion may be delivered to the systemic circulation intact and become available for potential therapeutic effects. The term bioavailability refers to the amount of a drug that is available after oral administration compared to that after intravenous administration. Factors influencing the bioavailability of a drug include patient compliance, disintegration of a capsule or a tablet, dissolution of drug into gastrointestinal fluid, stability of the drug in the gastrointestinal tract, absorption through the gastrointestinal mucosa, and first-pass metabolism in the liver. Problems seen in cancer patients, such as changes in gastrointestinal motility, mucosal damage from cancer therapy, and the use of other medications, can also affect bioavailability. Absorption of a drug may vary among patients receiving the same treatments, or within 1 patient from one course of treatment to another. This variability can account for some differences in toxicity, and possibly in tumor response. In most cases, such variations in drug bioavailability are not detected clinically because routine pharmacokinetic measurements are ...

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