Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

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182 Applying Pharmacogenomics in TherapeuticsKEY CONCEPTS• Recommendations for genetic testing prior to prescribing certain drugs inproduct labeling including warfarin, whose metabolism is affected by apatient’s CYP2C9 and VKORC1 genotypes.• The genetic polymorphisms of a drug transporter have been strongly implicatedin statin-induced myopathy. Although this may not be predictiveenough to use clinically, it has enhanced our understanding of this potentiallyserious adverse drug event.• β-Blocker pharmacogenomic research in heart failure has noticeably associatedwith various components of the adrenergic signaling pathway, andthese data have the potential to influence future drug development in heartfailure.• The clinical utilization of pharmacogenomics in cardiovascular disease ispromising, and clinical implementation has begun in certain centers, andthe findings will provide important insight into the challenges and futuredirections for cardiovascular pharmacogenomics.• Evaluation of the ultimate effects of a combination of polymorphisms indrug-metabolizing enzymes, drug transporters, drug targets, and/or diseaseprogression genes on cardiovascular drug response.• The potential for improvement in cardiovascular disease management mayarise from the applications of pharmacogenomics.INTRODUCTIONCardiovascular diseases remain the number one cause of death in the United Statesand will likely soon become the number one cause of death globally. At the sametime, new understandings of individual characteristics including genetic variationsare reforming our ability to treat various aspects of cardiovascular disorders.Although large randomized clinical trials clearly demonstrate population benefitswith many cardiovascular drugs, individual patients exhibit remarkable variability inefficacy and adverse effects. There are many sources of variability in response to drugtherapy, such as noncompliance and unknown drug interactions. This chapter focuseson genetic mechanisms contributing to variability in response to cardiovascular drugsused to treat hypertension, hyperlipidemia, arrhythmia, and heart failure (Figure 7.1).Since its inception, the field of pharmacogenetics has extended to study a wide rangeof cardiovascular drugs and has become a typical research discipline. Cardiovascularpharmacogenomics offers improved prevention of adverse drug events and treatmentoutcomes. Variants common in the population have been shown to modify targets,metabolism, and transport of drugs and could be utilized to predict an individual’streatment response. Evidence suggests that the common polymorphic variants of modifiergenes could influence drug response in cardiovascular disease (CVD) in a varietyof areas, including heart failure, arrhythmias, dyslipidemia, and hypertension. 1In the realm of cardiovascular pharmacogenetics, major advances have identifiedmarkers in each class for a variety of therapeutics, some with a potential to refiningpatient outcomes. Included in this chapter are the major pharmacogenetic variants
Drug Therapy of Cardiovascular Diseases183Cardiovascular drugsHypertensionHyperlipidemia(statins)Antiarrhythmics(quinidine)Heart failure(metoprolol,carvedilol)ACS(warfarin,clopidogrel,heparin, aspirin)ACEIs(perindopril)ARBs(losartan)CCBs(verapamil)ThiazidediureticsFIGURE 7.1 Cardiovascular disorders that reflect sources of pharmacogenomics variability.ACS, acute coronary syndrome; ACEIs, angiotensin-converting enzyme inhibitors; ARBs,angiotensin receptor blockers; CCBs, calcium channel blockers.associated with commonly used cardiovascular medications including warfarin,clopidogrel, and simvastatin. The data on warfarin, clopidogrel, and simvastatinwere found to be sufficient, well replicated, and clinically important. There are nowexamples of clinical application of pharmacogenetic data of these drugs to guide therapy.Other cardiovascular drug classes covered in this chapter that may be closest toclinical application of pharmacogenetics are the β-blockers, angiotensin-convertingenzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), diuretics, andantiarrhythmic drugs. Examples of cardiovascular drugs with evidence of relationshipbetween genetics and efficacy or toxicity are summarized in Table 7.1.WARFARINThe oral anticoagulant, warfarin, is prescribed for the long-term treatment and preventionof thromboembolic events. It has a very narrow and highly variable therapeuticrange. The dose requirement and risk of bleeding are influenced by intake ofvitamin K, illness, age, gender, concurrent medication, body surface, and genetics.In addition to the possible or demonstrated influence of a large number of genes, 2warfarin’s effect is influenced by two major genes: one involved in its biotransformation(CYP2C9) and the other involved in its mechanism of action (VKORC1).Warfarin is administered as a racemic mixture of the R and S stereoisomers.(S)-warfarin is two to five times more potent than (R)-warfarin and is mainlymetabolized by CYP2C9. (R)-warfarin is mainly metabolized via CYP3A4, withinvolvement of several other cytochrome P450 enzymes. 3 An investigation of thepharmacodynamics and pharmacokinetic properties of warfarin showed the additiveinvolvement of two genes to determine its dosage. One of these genes encodesCYP2C9, which is responsible for approximately 80% of the metabolic clearanceof the pharmacologically potent S-enantiomer of warfarin. There are threeallele types: CYP2C9*1, *2, and *3, and both CYP2C*2 and *3 cause a reductionin warfarin clearance. A 10-fold difference in warfarin clearance was observedbetween groups of individuals having the genotype of the highest metabolizer(CYPC9*1 homozygote) and lowest metabolizer (CYP2C9*3/*3). 4
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DedicationWe dedicate this book to
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viiiContentsChapter 10 Pharmacogeno
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EditorsXiaodong Feng, PhD, PharmD,
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ContributorsWeiguo Chen, PhDDepartm
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Concepts in Pharmacogenomics and Pe
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11 PharmacoeconogenomicsA Good Marr
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Pharmacoeconomics of Pharmacogenomi
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BIOMEDICAL SCIENCEApplying Pharmaco
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Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

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