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CHAPTER 7 | Implications of Drug–Nutrient Interactions and Pharmacology 105


Manufacturer drug labeling increasingly contains information on pharmacogenomic biomarkers that may alter drug pharmacokinetics or pharmacody- namics. As of 2020, pharmacogenomics information was found in 261 prescription drug labels.40


Between


2000 and 2020, one-quarter of new drug approvals in the United States contained pharmacogenomic bio- marker information in approved labeling. Oncology drugs had the highest rate, with nearly one-half of new oncology drug approvals containing pharma- cogenomic information.41


Pharmacogenomic testing


continues to become more affordable; with some insurance companies offering coverage, such testing is becoming more commonplace.42


In the future,


health care providers hope that pharmacogenomic information will be used routinely and proactively to predict and manage the large interindividual differ- ences in drug response.


Pharmacogenomic Alterations in Cytochrome P450 Enzyme Activity


Some of the leading pharmacogenomic polymor- phisms of interest that have evidence-based guidelines pertain to certain CYP drug-metabolizing enzymes found in the liver and small intestine. This superfam- ily of hemoproteins includes numerous isoforms with their own distinct nomenclature system.37,43


Although


dozens of CYP enzymes have been identified, the fam- ilies involved with the majority of drug metabolism in human beings are CYP1A, CYP2B, CYP2C, CYP2D, and CYP3A. CYP3A accounts for approximately 30% of hepatic CYP content and is involved in more than 50% of metabolism of drugs such as antidepressants, antipsychotics, anxiolytics, calcium channel block- ers, chemotherapeutics, immunosuppressants, mac- rolide antibiotics, opioids, and antihyperlipidemics (statins). Metabolism of the NHP St John’s wort, the antituberculosis agent rifampin, and azole antifungals also occurs via CYP3A.37,44 CYP2D6 represents approximately 2% to 5% of total CYP content of the liver but is responsible for the metabolism of 25% to 30% of prescription drugs. Individuals with two functional copies of genes coding for this enzyme have a normal phenotype of an extensive metabolizer. Substantial polymorphism exists with this enzyme, with some individuals having


one or two nonfunctional alleles coding for CYP2D6, resulting in a phenotype of intermediate metabolizer or poor metabolizer with reduced ability to metabo- lize substrates of this enzyme.45


This results in higher-


than-expected blood levels with standard doses of drugs that are normally metabolized via CYP2D6. Consequently, these individuals may have an exag- gerated response or experience adverse effects. On the other hand, individuals with extra functional copies of genes coding for the CYP2D6 enzyme have increased metabolic capacity and the phenotype of an ultrarapid metabolizer. This results in lower-than- expected levels of the drug in the blood with standard doses, possibly leading the individual to have a short- ened duration of action of poor therapeutic response to CYP2D6-metabolized drugs. CYP2C9 and CYP2C19 are also known to have substantial polymorphism, with poor, intermediate, extensive, and ultrarapid metabolizer phenotypes affecting the action of drugs that are substrates of these enzymes.41


Some individuals have CYP1A2 enzymes that may exhibit an extensive metabolizer phenotype generally but may be induced into a ultra rapid metab- olizer state in the presence of CYP1A2 inducers (eg, polycyclic aromatic hydrocarbons in tobacco smoke, or certain drugs such as rifampin) or with high dietary intake of barbecued meats, charbroiled meats, or cruciferous vegetables.46,47


Box 7.4 on page 106 lists


drugs that are substrates of the most common CYP enzymes involved in drug metabolism.43,48


Pharmacodynamic Gene Polymorphisms


Pharmacogenomic polymorphisms may also influ- ence the pharmacodynamic actions of drugs. Poly- morphisms in vitamin K epoxide reductase complex subunit VKORC1 may alter dosing requirements and explain up to 30% of variance in warfarin dosing.49 Research on pharmacodynamic-related biomarkers has investigated genetic variations for targets of anti- psychotic and antidepressant agents such as serotonin transporter SLC6A4, serotonin 2A


receptor HTR2A,


and dopamine receptor DRD2. Despite inclusion of results for these genes in some marketed pharmacog- enomic panels, most of these polymorphisms have not yet been validated for widespread clinical use.50


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