Interethnic Differences in Genetic Polymorphisms of CYP2D6 in the U.S. Population: Clinical Implications

Abstract

Key Words. CYP2D6 polymorphism • Hepatic metabolism • 5-HT 3 -receptor antagonist antiemetics • Genetic variability Learning Objectives After completing this course, the reader will be able to: 1. List the four different genotypes for CYP2D6 polymorphism. 2. Understand the potential effects of CYP2D6 polymorphism on the efficacy and safety for drugs metabolized via this enzyme. 3. List the ethnic groups that are most frequently affected by genetic variation of the CYP2D6 enzyme. Abstract DNA polymorphisms have been identified in the genes encoding a number of the cytochrome P450 (CYP) enzymes, leading to wide interindividual variation in drug clearance. CYP2D6 metabolizes a significant number of clinically used medications, and genetic vari-ants of the CYP2D6 isozyme that result in varying levels of metabolic activity are of clinical importance in some settings. The exact nature of the clinical effect caused by polymorphisms of the gene depends on the drug in question and the specific variant alleles expressed, as individual variants result in differing phenotypes with a range of levels of enzymatic activity. Compromised drug efficacy due to CYP2D6 varia-tion has been documented with a variety of agents, and this review considers a number of examples, includ-ing the 5-HT 3 -receptor antagonists, which are used in oncology supportive care for the prophylaxis of nausea and vomiting. CYP2D6 is involved in the metabolism of all of the most commonly available agents, except granis-etron, and their efficacy and side effects may therefore be affected by the CYP2D6 polymorphism. Significant interethnic differences in CYP2D6 allele frequencies have been demonstrated from stud-ies across many countries. However, incidences of poly-morphisms in the U.S. population have been challeng-ing to characterize because of the country's wide ethnic diversity. The CYP2D6 polymorphism may become more important as robust clinical tests become widely available and as the use of multiple medications and the attendant risk for drug–drug interactions increases. The Oncologist 2006;11:126–135 Access and take the CME test online and receive 1 AMA PRA category 1 credit at CME.TheOncologist.com