{"id":56572,"date":"2024-03-20T11:58:22","date_gmt":"2024-03-20T11:58:22","guid":{"rendered":"https:\/\/biomedpharmajournal.org\/?p=56572"},"modified":"2024-04-01T18:52:47","modified_gmt":"2024-04-01T18:52:47","slug":"personalized-medicine-of-flecainide-the-impact-of-the-cyp2d6-and-cyp1a2-polymorphism-on-responses-to-flecainide","status":"publish","type":"post","link":"https:\/\/biomedpharmajournal.org\/staging\/vol17no1\/personalized-medicine-of-flecainide-the-impact-of-the-cyp2d6-and-cyp1a2-polymorphism-on-responses-to-flecainide\/","title":{"rendered":"Personalized Medicine of flecainide (The impact of the CYP2D6 and CYP1A2 polymorphism on responses to flecainide)"},"content":{"rendered":"\n

Introduction<\/strong><\/p>\n\n\n\n

Anti-arrythmia\ndrug class IC called Flecainide is used to treat specific kinds\nof irregular heartbeats. Pharmacogenetics is the study of how a person’s\nresponse to medication is affected by genetic differences. In the case of\nflecainide, genetic variables may affect the drug’s effectiveness, the way it\nis metabolized, and the likelihood of side effects.  Genetic variations in some drug-metabolizing\nenzymes, such as the cytochrome P450 family of enzymes, may have an effect on\nthe body’s metabolism of flecainide. Variations in medication levels brought on\nby these enzyme polymorphisms may affect both treatment efficacy and safety.<\/p>\n\n\n\n

Flecainide therapeutic class<\/strong><\/p>\n\n\n\n

Flecainide\nis a class IC AAD. Flecainide is recommended\nin the management of patients without structural abnormalities, such as for (a)\nmanagement of newly emerging atrial fibrillation (AF)\n(class I recommendation, level A), (b) prevention of recurrent AF (class IIa\nrecommendation, level B) and (c) control of heart rhythm long-term (class I\nrecommendation, level A)1,2,3<\/sup> <\/p>\n\n\n\n

Structure<\/strong><\/p>\n\n\n\n\n\n
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Figure 1: Flecainide.4<\/sup><\/strong><\/p>\n

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Click here to view Figure<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

Pharmacokinetic<\/strong><\/p>\n\n\n\n

Flecainide acetate is slowly absorbed after oral administration; the Cmax is  reached in 3 hours (Tmax: 1-6 hours). Flecainide has a bioavailability of 90% to 95%.4<\/sup> There is no first-pass hepatic metabolism of flecainide. Flecainide is taken in doses of 200\u2013500 mg per day.5<\/sup> This medicine is metabolized by Cytochromes CYP2D6 and CYP1A2 in the liver. research by Manuel et al.<\/em>,  in 2005 found that flecainide metabolism is influenced by CYP2D6.6<\/sup> <\/p>\n\n\n\n

Flecainide taken orally has a elimination\nhalf-life (t1\/2) of around 13 hours (7\u201322 hours), which is unaffected by dose4<\/sup>  Most of the metabolites and flecainide are\nexcreted in urine.4,5,7<\/sup><\/p>\n\n\n\n

Metabolism of flecainide<\/strong><\/p>\n\n\n\n

Meta-O-dealkylated flecainide or the\nmeta-O-dealkylated lactam of flecainide is the principal product of flecainide\nmetabolism.6 <\/sup>The activity of meta-O-dealkylated flecainide is 20%\nthat of flecainide.5<\/sup>\nBoth of these metabolites are typically found as conjugates of glucuronide or\nsulfate.5<\/sup>\nThe metabolism of flecainide is dependent on CYP2D6 and CYP1A2.8<\/sup><\/p>\n\n\n\n\n\n
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Figure 2: Metabolite of flecainide <\/strong>4<\/sup><\/p>\n

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Click here to view Figure<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

Genetic Variability and Flecainide\nResponse<\/strong><\/p>\n\n\n\n

A person’s reaction to flecainide is\nmostly determined by hereditary variables. The way the body breaks down\nflecainide can be affected by variations in genes that code for\ndrug-metabolizing enzymes, such as cytochrome P450 enzymes.. Polymorphisms in\nthese genes can lead to variations in drug metabolism rates, potentially\nresulting in different levels of drug efficacy and side effects. Some\nindividuals may be genetically predisposed to particular arrhythmia types,\nwhich may affect how they respond to flecainide therapy. Pharmacologic  can make better treatment decisions and\npossibly avoid administering flecainide on individuals who might not respond\nwell by employing genetic testing to identify these predispositions<\/p>\n\n\n\n

The\neffect of CYP2D6 and CYP1A2 gene polymorphisms on flecainide pharmacokinetics.<\/strong><\/p>\n\n\n\n

CYP2D6 gene is located in\n22q13.2 exon 9. An enzyme\nfrom the cytochrome P450 superfamily is encoded by this gene. CPD6, CYP2D,\nCYP2DL1, CYPIID6, P450C2D, P450DB1, CYP2D7AP, CYP2D7BP, CYP2D7P2, CYP2D8P2, and\nP450-DB1 are other names for this gene. The monooxygenases known as cytochrome\nP450 proteins catalyze a variety of reactions that are involved in drug\nmetabolism and the synthesis of cholesterol, steroids, and other lipids. This\nendoplasmic reticulum-localized protein is known to metabolize up to 25% of commonly\nprescribed pharmaceutical.9<\/sup>\nCYP1A2 gene is located in 15q24.1\nexon 7. CYP1A2 is a monooxygenase that catalyzes numerous reactions implicated\nin drug metabolism and cholesterol, steroid, and lipid synthesis.  The enzyme’s endogenous substrate is unknown.  This enzyme’s xenobiotic substrates include\naflatoxin B1, acetaminophen and caffeine,. 10<\/sup><\/p>\n\n\n\n

An enzyme called a CYP2D6\nis involved in the metabolism of many different types of medications.. This\nenzyme metabolize many drugs, among others: <\/em>\u03b2-Adrenoceptor blockers (metoprolol, propranolol,timolol),\nNeuroleptics (haloperidol, risperidone etc), Antiarrhythmic drugs (propafenone\netc).1<\/sup><\/em>1<\/sup><\/em>\n<\/em>This enzyme metbaolize amyitryptiline and\nothers anti depressant such as nortryptilone, paroxetine and others.  1<\/sup><\/em>1,12<\/sup><\/em> <\/sup><\/em> The CYP2D6 polymorphism describes genetic\nchanges within the CYP2D6 gene that affect an individual’s level of enzyme\nactivity. Based on their CYP2D6 enzyme activity, people can be categorized into\nseveral phenotypes as a result of these genetic variances. Genetic\npolymorphisms give rise to a variety of CYP2D6 phenotypes. These phenotypes\nfall into the general categories of poor metabolizers (PMs), intermediate\nmetabolizers (IMs), normal metabolizers (NMs), and ultra rapid metabolizers\n(UMs). The degree of CYP2D6 enzyme activity varies depending on the phenotypic,\nwhich can have a big impact on how people metabolize medications. The metabolism of flecainide is affected by variations in CYP2D6\nactivity. CYP2D6 uses flecainide as a substrate. The hepatic enzymes CYP2D6 and\nCYP1A2 convert flecainide to m-O-dealkylated flecainide (MODF), which is then\noxidized to m-O-dealkylated lactam. Flecainide is eliminated in the urine in an\nunchanged form in about 30% of the whole dose.1<\/sup>3<\/sup>,1<\/sup>4<\/sup>,1<\/sup>5<\/sup> Flecainide clearance is\ndecreased by 21% in intermediate metabolizers (IM) and by 42% in poor\nmetabolizers (PM) due to impaired CYP2D6 activity.1<\/sup>6<\/sup>,1<\/sup>7<\/sup> Patients with reduced CYP2D6 activity, for example on IMs\nand PMs show decreased metabolism.1<\/sup>3<\/sup>  The alleles *10, *17, *36, and *41 caused a\ndecrease in enzyme activity. There is no enzyme activity in alleles *3, *4, *5,\n*6, *7, *8, *11, *12, *13, *14, *15, *16, *18, *19, *20, *21, *38, *40, *42,\n*44, *56, and *62. This allele were responsible for the PM phenotype in both\nhomozygotes and heterozygotes. CYP2D6*2, *3, *4, *5, *10, *17, and *41 are\nthought to cause changes in drug clearance and response.1<\/sup>8<\/sup> <\/p>\n\n\n\n

Riset by Miao Hu 2012 found that  <\/strong>The\npharmacokinetics of flecainide did not differ significantly between CYP2D6 *10\ngenotypes. Comparing individuals with CYP1A2*1A\/1F and at least one CYP2D6\nvariant allele, those with CYP1A2*1F tended to have greater clearance of\nflecainide and lower systemic exposure.19<\/sup><\/p>\n\n\n\n

Clinical Implications<\/strong><\/p>\n\n\n\n

Because it can affect the effectiveness\nand safety of numerous drugs, the CYP2D6 polymorphism has important clinical\nimplications.  Individual with PMs of\nCYP2D6 may have undesirable side effects or adverse effect. Frequently reported\nadverse effects of flecainide are dizziness (30%) and visual disturbances\n(28%), which often occur simultaneously. Side effects such as headaches,\nnausea, dyspnoea, and chest pain occur in 6-9% of patients.20<\/sup>.\nFlecainide-induced constipation is more common (21, %) in PM patients than in\nEM patients without the conditions .6<\/sup>  Research by Nutulaghanti et al,<\/em> 2022 (case report) showed that\nover effect of flecainide can cause LBBB (left bundle branch block). Flecainide toxicity occurs due\nto sodium channel toxicity. This causes a decrease in electrical conduction in\nthe left ventricular myocardium leading to ventricular LBBB21<\/sup>.\nHowever, individual with UMs may metabolize\nmedications too quickly, resulting in inadequate therapeutic doses.<\/p>\n\n\n\n

Challenges and Future Directions<\/strong><\/p>\n\n\n\n

Using flecainide and other drugs to\nimplement personalized medicine techniques presents difficulties like the price\nof genetic testing, the requirement for established criteria, and the\ninterpretation of complicated genetic data. The advantages of adjusting\nflecainide treatment to specific patients, however, become more apparent as\ngenomic technologies develop and our knowledge of pharmacogenomics increases.<\/p>\n\n\n\n

Conclusion<\/strong><\/p>\n\n\n\n

There is a suspicion that the metabolic\nprocess of flecainide is facilitated by the enzyme CYP2D6, whilst the impact of\nCYP1A2 is minor. The role of CYP2D6 in metabolic of Flecainide is clear, mean\nwhile the precise involvement of CYP1A2 in the metabolic process of Flecainide\nremains uncertain. Limited study has been conducted thus far regarding the\ninvolvement of CYP1A2 in the metabolism of flecainide, as well as the impact of\nCYP1A2 polymorphisms on alterations in flecainide pharmacokinetics.<\/p>\n\n\n\n

Acknowledgment<\/strong><\/p>\n\n\n\n

Cancellor of Universitas Muhammadiyah Surakarta, Indonesia.<\/p>\n\n\n\n

Conflict of Interest<\/strong><\/p>\n\n\n\n

None to declare <\/p>\n\n\n\n

Funding Source<\/strong><\/p>\n\n\n\n

This research was funded by Universitas Muhammadiyah Surakarta, Indonesia with no: 301.49\/A.3-III\/FK\/2023<\/p>\n\n\n\n

Reference\u2019s <\/strong><\/p>\n\n\n\n

  1. Camm AJ, Lip GYH, De Caterina R, et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur Heart J. 2012;33:2719\u20132747. <\/li>
  2. Fuster V, Ryd\u00e9n LE, Cannom DS, et al. ACC\/AHA\/ESC 2006 guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology\/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to revise the 2001 guidelines for the management of patients with atrial fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation. 2006;114:e257\u2013e354. <\/li>
  3. Anderson JL, Halperin JL, Albert NM, et al. Management of patients with atrial fibrillation (compilation of 2006 ACCF\/AHA\/ESC and 2011 ACCF\/AHA\/HRS recommendations): a report of the American College of Cardiology\/American Heart Association Task Force on practice guidelines. J Am Coll Cardiol. 2013;61:1935\u20131944. 
     CrossRef <\/a><\/li>
  4. Conard GJ, Ober RE. Metabolism of flecainide. Am J Cardiol 1984;53:41b\u201351b.
     CrossRef <\/a><\/li>
  5. Roden DM, Woosley RL. Drug therapy. Flecainide. N Engl J Med 1986;315:36\u201341
     CrossRef <\/a><\/li>
  6. Manuel Mart\u00ednez-Sell\u00e9s,Isabel Castillo,Pilar Montenegro,Mar\u00eda L. Mart\u00edn,Jes\u00fas Almendral, and Mar\u00eda Sanjurjo,  Pharmacogenetic Study of the Response to Flecainide and Propafenone in Patients With Atrial Fibrillation, Rev Esp Cardiol. 2005;58(6):745-8
     CrossRef <\/a><\/li>
  7. Holmes B, Heel RC. Flecainide. A preliminary review of its pharmacodynamic properties and therapeutic efficacy. Drugs. 1985;29:1\u201333. 
    CrossRef <\/a><\/li>
  8. Andrikopoulos GK, Pastromas S, Tzeis S: Flecainide: Current status and perspectives in arrhythmia management. World J Cardiol. 2015;7(2):76-85.
    CrossRef <\/a><\/li>
  9. CYP2D6 cytochrome P450 family 2 subfamily D member 6 [ Homo sapiens<\/em> (human) ] https:\/\/www.ncbi.nlm.nih.gov\/gene\/1565<\/li>
  10. CYP1A2  cytochrome P450 family 1 subfamily A member 2, https:\/\/www.ncbi.nlm.nih.gov\/gene\/1544  <\/li>
  11. Leif Bertilsson, Marja-Liisa Dahl, Per Dal\u00e9n, and Ayman Al-Shurbaji, Molecular genetics of CYP2D6: Clinical relevance with focus on psychotropic drugs, Br J Clin Pharmacol. 2002; 53(2): 111\u2013122.
     CrossRef <\/a><\/li>
  12. Sutrisna,EM, Pharmacogenetic Of Amitriptyline – Review Article,  J.Bio.Innov. 2021;10(0): 1587-1595.<\/li>
  13. Doki K, Homma M, Kuga K, Kusano K, Watanabe S, Yamaguchi I, Kohda Y. Effect of CYP2D6 genotype on flecainide pharmacokinetics in Japanese patients with supraventricular tachyarrhythmia. Eur J Clin Pharmacol. 2006;62:919\u201326.
     CrossRef <\/a> <\/li>
  14. Gross AS, Mikus G, Fischer C, Hertrampf R, Gundert-Remy U, Eichelbaum M. Stereoselective disposition of flecainide in relation to the sparteine\/debrisoquine metaboliser phenotype. Br J Clin Pharmacol. 1989;28:555\u201366. 
     CrossRef <\/a><\/li>
  15. Gross AS, Mikus G, Fischer C, Eichelbaum M. Polymorphic flecainide disposition under conditions of uncontrolled urine flow and pH. Eur J Clin Pharmacol. 1991;40:155\u201362. 
     CrossRef <\/a><\/li>
  16. Birgersdotter UM, Wong W, Turgeon J, Roden DM. Stereoselective genetically-determined interaction between chronic flecainide and quinidine in patients with arrhythmias. Br J Clin Pharmacol. 1992;33:275\u201380. 
     CrossRef <\/a><\/li>
  17. Doki K, Homma M, Kuga K, Aonuma K, Sakai S, Yamaguchi I, Kohda Y. Gender-associated differences in pharmacokinetics and anti-arrhythmic effects of flecainide in Japanese patients with supraventricular tachyarrhythmia. Eur J Clin Pharmacol. 2007;63:951\u20137. 
     CrossRef <\/a><\/li>
  18. Shu-Feng Zhou, Polymorphism of human cytochrome P450 2D6 and its clinical significance: Part I, Clin Pharmacokinet,. 2009;48(11):689-723.
     CrossRef <\/a><\/li>
  19. Miao Hu <\/sup>, Ya-Ling Yang, Benny S P Fok, Sze-Wa Chan, Tanya T W Chu, Emily W M Poon, Ophelia Q P Yin, Vincent H L Lee, Brian Tomlinson. Effects of CYP2D6*10, CYP3A5*3, CYP1A2*1F, and ABCB1 C3435T polymorphisms on the pharmacokinetics of flecainide in healthy Chinese subjects. Drug Metabol Drug Interact,. 2012; 27(1):33-9.
    CrossRef<\/a><\/li>
  20. Garry, D.G, Sullivan, JY, Extracardiac adverse effects of flecainide, Am J Cardiol. 1984;53(5):101B-105B.
     CrossRef <\/a><\/li>
  21. Nuthulaganti <\/sup>SR,  Zhang,<\/sup>Y, Akinjogbin, T, Esmail, K ,, <\/sup>Flecainide-Induced Left Bundle Branch Block, Case reports, Cureus, . 2022 Apr 22;14(4):e24385.
     CrossRef <\/a><\/li><\/ol>\n","protected":false},"excerpt":{"rendered":"

    Introduction Anti-arrythmia drug class IC called Flecainide is used to […]<\/p>\n","protected":false},"author":15,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[113],"tags":[],"class_list":["post-56572","post","type-post","status-publish","format-standard","hentry","category-vol17no1"],"_links":{"self":[{"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/posts\/56572","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/users\/15"}],"replies":[{"embeddable":true,"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/comments?post=56572"}],"version-history":[{"count":5,"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/posts\/56572\/revisions"}],"predecessor-version":[{"id":57376,"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/posts\/56572\/revisions\/57376"}],"wp:attachment":[{"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/media?parent=56572"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/categories?post=56572"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/tags?post=56572"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}