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KEY CONCEPTS

KEY CONCEPTS

  • image Genetic variation contributes to pharmacokinetic and pharmacodynamic drug properties.

  • image Genetic variation occurs for drug metabolism, drug transporter, and drug target proteins, as well as disease-associated proteins that may impact drug response.

  • image Single-nucleotide polymorphisms are the most common gene variations associated with drug response.

  • image Genetic polymorphisms may influence drug effectiveness and risk for toxicity.

  • image Pharmacogenetics is the study of the impact of genetic polymorphisms on drug response.

  • image The goals of pharmacogenetics are to optimize drug efficacy and limit drug toxicity based on an individual’s DNA.

  • image Gene therapy aims to cure disease caused by genetic defects by changing gene expression.

  • image Inadequate gene delivery and expression and serious adverse effects are obstacles to successful gene therapy.

PRECLASS ACTIVITY

Preclass Engaged Learning Activity

Visit the https://tinyurl.com/wdjr6xd.org/ website. Enter one of the following drugs in the search box: warfarin, codeine, paroxetine, clopidogrel, or carbamazepine. Review available dosing guidelines, labeling information, and one of the clinical annotations. This website is useful to enhance student understanding of available resources for pharmacogenetic information.

INTRODUCTION

Great variability exists among individuals in response to drug therapy, and it is difficult to predict how effective or safe a medication will be for a particular patient. For example, when treating a patient with hypertension, it may be necessary to try several agents or a combination of agents before achieving adequate blood pressure control with acceptable tolerability. A number of clinical factors are known to influence drug response, including age, body size, kidney and liver function, and concomitant drug use. However, considering these factors alone is often insufficient in predicting the likelihood of drug efficacy or safety for a given patient. For example, identical antihypertensive therapy in two patients of similar age, sex, race, and with similar medical histories and concomitant drug therapy may produce inadequate blood pressure reduction in one patient and symptomatic hypotension in the other.

image image The observed interpatient variability in drug response may result largely from genetically determined differences in drug metabolism, drug distribution, and drug target proteins. The influence of heredity on drug response was demonstrated as early as 1956 with the discovery that an inherited deficiency of glucose-6-phosphate dehydrogenase (G6PD) was responsible for hemolytic reactions to the antimalarial drug primaquine (Fig. e6-1). Variations in genes encoding cytochrome P450 (CYP) and other drug-metabolizing enzymes are now well recognized as causes of interindividual differences in plasma concentrations of certain drugs. These variations may have serious implications for narrow-therapeutic-index drugs such as warfarin, phenytoin, and mercaptopurine. Other variations associated with drug response occur in genes for drug transporters such as the solute carrier organic anion transporter (OAT) family member 1B1 (SLCO1B1) and organic cation transporter 1 (OCT1), as well as drug targets such as receptors, enzymes, and proteins involved in intracellular signal transduction. Genetic variations for drug metabolizing enzymes and drug transporter proteins may influence drug disposition, thus altering pharmacokinetic drug ...

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