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Chapter 5: Pharmacogenomics

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A 59-year-old man with acute coronary syndrome is admitted to the hospital for emergency percutaneous insertion of a coronary stent. Which of the following drugs might cause unexpected results based on the patient’s CYP2C19 genotype?

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(A) Clopidogrel

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(B) Codeine

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(C) Prasugrel

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(D) Ticagrelor

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(E) Warfarin

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Clopidogrel is a prodrug that must be metabolized to an active platelet-inhibiting metabolite by CYP2C19. Poor metabolizers achieve inadequate platelet inhibition, and EMs and UMs may have excess effect and bleed. Prasugrel and ticagrelor do not require P450 activation and are not subject to this risk. The answer is A.

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A 62-year-old woman with advanced colon cancer is treated with intravenous 5-fluorouracil. Within a few days, she develops severe diarrhea, and within a week, she shows severe neutropenia. Which of the following polymorphisms is most likely to be responsible?

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(A) CYP2D6*1x3

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(B) CYP2C19*2

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(C) CYP2C9*3

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(D) DYPD*2A

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(E) UGT1A1*28

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CYP2D6*1x3 is a gain-of-function allele and is associated with increased effect and toxicity of codeine. CYP2C19*2 is a nonfunctional allele associated with reduced efficacy of clopidogrel. CYP2C9*3 with a reduced function allele of VCORC1 is associated with reduced warfarin clearance. UGT1A1*28 is a reduced function allele for uridine 5′-diphospho-(UDP) glucuronosyltransferase and enhances irinotecan toxicity. 5-Fluorouracil is cleared by dihydropyrimidine dehydrogenase (DPD). The DYPD*2A allele is nonfunctional. The answer is D.

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A 38-year-old man is being treated for HIV-induced acquired immunodeficiency syndrome (AIDS). When abacavir therapy is begun, he develops a severe skin rash. Which of the following pharmacogenomic diagnoses might explain this skin rash?

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(A) CYP2D6*3 (PM)

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(B) CYP3A5*3 (PM)

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(C) HLA-B*57:01 (EM)

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(D) SLCO1B1*5 (PM)

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Poor metabolizers of the CYP2D6*3 genotype are prone to reduced efficacy of codeine. Poor metabolizers of the CYP3A5*3 type show reduced tacrolimus clearance. Simvastatin toxicity (myopathy) is enhanced in SLCO1B1 poor metabolizers. Enhanced metabolizers of the HLA-B*57:01 type are prone to abacavir rashes and flucloxacillin liver damage. The answer is C.

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A college student volunteers to have his genome decoded as part of a population-wide study of polymorphisms. He receives a call from the principal investigator informing him that his genome unexpectedly contains an important single nucleotide polymorphism. Which ...

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