CYP2D6, CYP2C19, CYP3A4/5, and dihydropyrimidine dehydrogenase are among the drug-metabolizing enzymes most carefully studied (Table 5–1).
TABLE 5–1Polymorphisms associated with altered drug responses. ||Download (.pdf) TABLE 5–1 Polymorphisms associated with altered drug responses.
|Functional Element ||Alleles or SNPs of Major Importance ||Examples of Drugs Affected |
|Phase I enzyme || || |
|CYP2C9 ||*2, *3: decreased function ||Warfarin, phenytoin, antidiabetic sulfonylurea metabolism slowed, toxicity increased |
|CYP2C19 || |
*17: increased function,
*2, *3: decreased function
|Increased or decreased clopidogrel active metabolite |
|CYP2D6 || |
*1, *2: increased function
*3, *4, *5: decreased function
|Codeine converted to morphine. Increased function associated with increased toxicity; decreased function associated with decreased analgesia. Increased toxicity of many other drugs |
3A5 (SNPs more common in 3A5)
*1, *8, *11, *13, *16, *17: decreased function
*3, *5, *6, *7: decreased function
|Metabolism of some dihydropyridines, cyclosporine, tacrolimus reduced; increased toxicity |
|Dihydropyrimidine dehydrogenase (DPD) ||DPYD *2A, *13, rs67376798: reduced function ||Increased toxicity from pyrimidine cancer chemotherapeutic agents, eg, 5-FU |
|Phase II enzyme || || |
|UGT1A1 ||UGT1A1*28 ||Increased irinotecan toxicity |
|TPMT ||*2, *3 ||Increased thiopurine (azathioprine, 6-mercaptopurine, 6-thioguanine) toxicity |
|G6PD ||Mediterranean, Canton, Kaiping: decreased function ||Greatly increased susceptibility to hemolysis and other toxicities from oxidative stressors but increased resistance to malaria |
|Transporters || || |
|OATP (P-gp, etc) ||rs4149056: decreased function ||Increased risk of simvastatin myopathy. Many other drugs but effects inconclusive |
|Receptors || || |
|Beta1 adrenoceptor ||ADRB1 Arg389Gly ||Increased efficacy of metoprolol |
This enzyme is responsible for the hepatic metabolism of 20% of commonly used drugs. More than 100 polymorphisms of the CYP2D6 gene have been discovered, but only 9 are common. CYP2D6 polymorphisms are especially important in patients receiving codeine because this enzyme converts codeine to its active metabolite, morphine. Several deaths due to respiratory depression have been reported in children who were believed to be ultrarapid metabolizers.
CYP2C19 is responsible for the hepatic metabolism of a small number of very important drugs (clopidogrel, propranolol, omeprazole, diazepam, and tricyclic antidepressants). Because reduced metabolism of clopidogrel results in lower concentrations of its active metabolite, reduced function polymorphisms in this enzyme reduce the efficacy of clopidogrel and increase the risk of clotting in patients with coronary artery disease. Conversely, gain of function results in increased risk of bleeding. Poor metabolizers and IMs should receive alternative drugs prasugrel or ticagrelor, not clopidogrel.
CYP3A4/5 are responsible for the metabolism of over 50% of drugs in common use. Some polymorphisms with important ethnic variability have been described, but relatively few appear to alter pharmacokinetics to a clinically significant degree.
D. Dihydropyrimidine Dehydrogenase (DPD)
DPD is responsible for the clearance of 5-fluorouracil (5-FU), a first-line prodrug agent for the treatment of colorectal cancer. Capecitabine and tegafur are oral prodrugs converted in the body to 5-FU. In the body, 5-FU is converted to cytotoxic 5-fluorouridine 5′-monophosphate (5-FUMP) and 5-fluoro-2′-deoxyuridine-5′-monophosphate (5-FdUMP) (see Chapter 54). Nonfunctional polymorphisms in the DYPD gene result in increased toxicity and require reduced dosage.
E. Multiple Enzyme Polymorphisms: CYP2C9 and VCORC1
CYP2C9 and vitamin K epoxide reductase complex subunit 1 (VCORC1) are responsible for the inactivation of S-warfarin. Some mutations of the VCORC1 gene lead to spontaneous bleeding disorders. Reduced function polymorphisms in both genes result in increased warfarin action and enhanced risk of bleeding. Algorithms have been developed to predict the optimal dosage of warfarin, but clinical trials of these algorithms have not shown improved anticoagulant control thus far.