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?
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.
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?
CYP2D6*1x3 is a gain-of-function allele enhanced by 3 copies (“x3”) 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 DPYD*2A allele is nonfunctional. The answer is D.
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?
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.
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 of the following polymorphisms is associated with risk of hemolysis and increased resistance to malaria?
CYP2D6*3 is associated with reduced codeine efficacy. CYP2D19*2 results in reduced clopidogrel conversion to its active metabolite. TPMT*2 is associated with decreased clearance of 6-mercaptopurine and increased toxicity. UGT1A1*28 results in decreased clearance and increased toxicity of SN-38, the active metabolite of irinotecan. G6PD-(A)–Canton is a reduced function allele of the glucose-6-phosphate dehydrogenase gene that decreases intracellular stores of glutathione, increasing the risk of hemolysis but reducing susceptibility to malaria. The answer is E.
A 7-year-old child is brought to the emergency department in coma with cyanosis. Her mother states that the girl was given codeine with acetaminophen because of severe bruising after a fall. Shortly after the first dose, the child became unresponsive and “turned blue.” Which of the following alleles might be responsible for this presentation?
As noted in answer 4, SNPs in CYP2D6 may increase or decrease the efficacy and toxicity of codeine because the CYP2D6 enzyme is responsible for conversion of codeine to its active metabolite, morphine. CYP2D6*1xN and *2xN are gain-of-function alleles with increased copy number polymorphisms that result in more efficient conversion to morphine and increased risk of opioid-induced respiratory depression. The answer is A.