Association between CYP2C9 and CYP2C19 Polymorphism, Metabolism, and Neurotoxicity after Administration of Phenytoin: A Systematic Review
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Abstract
Abstract—Phenytoin is an antiepileptic drug (AED) metabolized by cytochrome P450 enzymes, especially by CYP2C9 (90%) and CYP2C19 (10%), where both enzymes are polymorphic so that they can undergo polymorphism and it can change the metabolic rate of the drug. Phenytoin is one of the drugs whose risk of side effects may increase due to its narrow therapeutic window of 10-20 µg/mL if the metabolism is slow. The main literature was taken from publications through the library databases in 2017 – 2021. Studies and reviews describing the metabolism, CYP2C9 and CYP2C19 polymorphisms, and neurotoxicity of phenytoin were included, and unrelated research were excluded. There were 18 of 853 articles describing CYP2C9 and CYP2C19 polymorphisms, metabolism, and neurotoxicity events associated with phenytoin used. The authors conclude that based on the results from various literature, there is an association between CYP2C9 and CYP2C19 polymorphism, metabolism, and neurotoxicity after Phenytoin administration with CYP2C9*2 and CYP2C9*3 types of polymorphisms for CYP2C9 and CYP2C19*2 and CYP2C19*3 types for CYP2C19*3 enzymes which can slow down the phenytoin metabolism and increase its concentration in serum so that the risk of causing neurotoxicity.
Keywords: CYP2C9, CYP2C19,metabolism, neurotoxicity, phenytoin
Abstrak—Fenitoin merupakan obat antibangkitan yang dimetabolisme oleh enzim sitokrom P450 terutama oleh CYP2C9 (90%) dan CYP2C19 (10%), dimana kedua enzim tersebut bersifat polimorfik sehingga dapat mengalami polimorfisme dan dapat mempengaruhi laju metabolisme obat. fenitoin merupakan salah satu obat yang risiko efek sampingnya dapat meningkat jika metabolismenya lambat karena jendela terapeutiknya yang sempit, yaitu 10-20 µg/mL. Literatur utama diambil dari publikasi melalui database perpustakaan tahun 2017 – 2021. Penelitian dan ulasan yang menggambarkan metabolisme, polimorfisme CYP2C9 dan CYP2C19, dan neurotoksisitas fenitoin, dan penelitian yang tidak terkait dikeluarkan. Terdapat 18 dari 853 artikel yang menjelaskan polimorfisme CYP2C9 dan CYP2C19, metabolisme, dan kejadian neurotoksisitas terkait dengan fenitoin yang digunakan. Peneliti menyimpulkan bahwa berdasarkan hasil dari berbagai literatur, terdapat hubungan antara polimorfisme, metabolisme, dan neurotoksisitas CYP2C9 dan CYP2C19 setelah pemberian fenitin dengan jenis polimorfisme CYP2C9*2 dan CYP2C9*3 untuk CYP2C9 dan CYP2C19*2 dan CYP2C19*3 jenis enzim CYP2C19*3 yang dapat memperlambat metabolisme fenitoin dan meningkatkan konsentrasinya dalam serum sehingga berisiko menyebabkan neurotoksisitas.
Kata kunci: CYP2C9, CYP2C19, fenitoin, metabolisme, neurotoksisitas
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References
Patocka J, Wu Q, Nepovimova E, Kuca K. Phenytoin – An anti-seizure drug: Overview of its chemistry, pharmacology and toxicology. Food Chem Toxicol [Internet]. 2020;142(January):111393. Available from: https://doi.org/10.1016/j.fct.2020.111393
Silvado CE, Terra VC, Twardowschy CA. CYP2C9 polymorphisms in epilepsy: Influence on phenytoin treatment. Pharmgenomics Pers Med. 2018;11:51–8.
Franco V, Perucca E. CYP2C9 polymorphisms and phenytoin metabolism: Implications for adverse effects. Expert Opin Drug Metab Toxicol. 2015;11(8):1269–79.
Ahmed S, Zhou Z, Zhou J, Chen SQ. Pharmacogenomics of Drug Metabolizing Enzymes and Transporters: Relevance to Precision Medicine. Genomics, Proteomics Bioinforma [Internet]. 2016;14(5):298–313. Available from: http://dx.doi.org/10.1016/j.gpb.2016.03.008
Yaşar Ü. The role of pharmacogenetics of cytochrome P450s in phenytoin-induced DRESS syndrome. Cent Eur J Immunol. 2018;43(2):220–1.
Iorga, A; Horowitz B. Phenytoin Toxicity [Internet]. StatPearls Publishing, Treasure Island (FL); 2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK482444/#!po=96.8750
Thaker SJ, Gandhe PP, Godbole CJ, Bendkhale SR, Mali NB, Thatte UM, et al. A prospective study to assess the association between genotype, phenotype and Prakriti in individuals on phenytoin monotherapy. J Ayurveda Integr Med [Internet]. 2017;8(1):37–41. Available from: http://dx.doi.org/10.1016/j.jaim.2016.12.001
Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. BMJ. 2021;372.
Whiting, P. F., Rutjes, A. W., Westwood, M. E., Mallett, S., Deeks, J. J., Reitsma, J. B., Leeflang, M. M., Sterne, J. A., Bossuyt, P. M., & QUADAS-2 Group, 2011. Quadas-2: a revised tool for the quality assessment of diagnostic accuracy studies. Annals of internal medicine. 155(8), 529–536.
Khalyfa A, Sanz-Rubio D. Genetics and extracellular vesicles of pediatrics sleep disordered breathing and epilepsy. Int J Mol Sci. 2019;20(21).
Juvale IIA, Che Has AT. Possible interplay between the theories of pharmacoresistant epilepsy. Vol. 53, European Journal of Neuroscience. 2021. 1998–2026 p.
Kam H, Jeong H. Pharmacogenomic biomarkers and their applications in psychiatry. Genes (Basel). 2020;11(12):1–22.
Božina N, Sporiš IŠ, Božina T, Klarica-Domjanović I, Tvrdeić A, Sporiš D. Pharmacogenetics and the treatment of epilepsy: What do we know? Pharmacogenomics. 2019;20(15):1093–101.
Chang WC, Hung SI, Carleton BC, Chung WH. An update on CYP2C9 polymorphisms and phenytoin metabolism: implications for adverse effects. Expert Opin Drug Metab Toxicol [Internet]. 2020;0(0):723–34. Available from: https://doi.org/10.1080/17425255.2020.1780209
Dagenais R, Wilby KJ, Elewa H, Ensom MHH. Impact of Genetic Polymorphisms on Phenytoin Pharmacokinetics and Clinical Outcomes in the Middle East and North Africa Region. Drugs R D. 2017;17(3):341–61.
Balestrini S, Sisodiya SM. Pharmacogenomics in epilepsy. Neurosci Lett [Internet]. 2018;667:27–39. Available from: http://dx.doi.org/10.1016/j.neulet.2017.01.014
Balestrini S, Sisodiya SM. Personalized treatment in the epilepsies: challenges and opportunities. Expert Rev Precis Med Drug Dev [Internet]. 2018;3(4):237–47. Available from: https://doi.org/10.1080/23808993.2018.1486189
Reddigari R, Naveen Prasad S, Bhuma V, Sarma P, Anumolu A. CYP2C9 polymorphisms are associated with phenytoin toxicity in South-Indian epileptic patients. J Dr NTR Univ Heal Sci. 2020;9(2):92.
Orsini A, Esposito M, Perna D, Bonuccelli A, Peroni D, Striano P. Personalized medicine in epilepsy patients. J Transl Genet Genomics. 2018;1–18.
Vázquez M, Fagiolino P. The role of efflux transporters and metabolizing enzymes in brain and peripheral organs to explain drug-resistant epilepsy. Epilepsia Open. 2021;(May):1–12.
Fricke-Galindo I, Jung-Cook H, LLerena A, López-López M. Pharmacogenetics of adverse reactions to antiepileptic drugs. Neurol (English Ed [Internet]. 2018;33(3):165–76. Available from: http://dx.doi.org/10.1016/j.nrleng.2015.03.021
Quignot N, Więcek W, Lautz L, Dorne J Lou, Amzal B. Inter-phenotypic differences in CYP2C9 and CYP2C19 metabolism: Bayesian meta-regression of human population variability in kinetics and application in chemical risk assessment. Toxicol Lett. 2021;337:111–20.
Cucchiara F, Ferraro S, Luci G, Bocci G. Relevant pharmacological interactions between alkylating agents and antiepileptic drugs: preclinical and clinical data. Pharmacol Res [Internet]. 2021;175(November 2021):105976. Available from: https://doi.org/10.1016/j.phrs.2021.105976
Kuban W, Daniel WA. Cytochrome P450 expression and regulation in the brain. Drug Metab Rev [Internet]. 2021;53(1):1–29. Available from: https://doi.org/10.1080/03602532.2020.1858856
Marcath LA, Pasternak AL, Hertz DL. Challenges to assess substrate-dependent allelic effects in CYP450 enzymes and the potential clinical implications. Pharmacogenomics J [Internet]. 2019;19(6):501–15. Available from: http://dx.doi.org/10.1038/s41397-019-0105-1
Esposito M, Lagorio I, Peroni D, Bonuccelli A, Orsini A, Striano P. Genomic sequencing in severe epilepsy: a step closer to precision medicine. Expert Rev Precis Med Drug Dev [Internet]. 2020;5(2):101–8. Available from: https://doi.org/10.1080/23808993.2020.1732203
Torabian P, Dehestani M, Morshedi Rad D, Peiravi S, Aghaie-Hakkak M, Ashraf H. Genomic and Personalized Medicine Perspective in Genetic Generalized Epilepsy. Arch Iran Med. 2019;22(9):516–26.
Pratt VM, Cavallari LH, Del Tredici AL, Hachad H, Ji Y, Moyer AM, et al. Recommendations for Clinical CYP2C9 Genotyping Allele Selection: A Joint Recommendation of the Association for Molecular Pathology and College of American Pathologists. J Mol Diagnostics [Internet]. 2019;21(5):746–55. Available from: https://doi.org/10.1016/j.jmoldx.2019.04.003
Shah RR, Gaedigk A. Precision medicine: does ethnicity information complement genotype-based prescribing decisions? Ther Adv Drug Saf. 2018;9(1):45–62.
Dhiman V. Molecular genetics of epilepsy: A clinician’s perspective. Ann Indian Acad Neurol. 2017;20(2):96–102.
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