Document Type : Original Article
Department of Gynecology and Obstetrics, Basaksehir Cam and Sakura City Hospital, University of Health Science, Istanbul, Turkey
Department of Pharmacy, Faculty of Medical, Tianjin Medical University, Tianjin P.R. China
Department of Pharmacy, Faculty of Medical, Gasha technical Institute, Erbil, Iraq
Department of Biology, College of Education, Salahaddin University-Erbil, Erbil, Iraq
Department of Pharmacy, Faculty of Medical, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
Research and Development Department, Giga Biotics, San Diego, California, USA
Rivaroxaban is an anticoagulant drug that prevents forming of blood clots. In addition, it can be administered to prevent and treat thrombotic diseases such as atrial fibrillation, cardiac arrhythmia, heart valve disease, orthopedic surgery, and thrombophilia to reduce the risk of thrombosis. Various factors such as age, gender, diet, medications, and genetic factors effectively determine the dose of rivaroxaban. Genetic variability in drug-metabolizing enzymes, including the cytochrome P450 (CYP450) enzymes and especially CYP3A4, has been associated with rivaroxaban response. The current study aimed to identify the frequency of CYP3A4 common polymorphisms, as well as their association with rivaroxaban response in 100 patients of Arab descent (48.6% female). CYP3A4 gene polymorphisms were examined by the PCR-RFLP method, and the findings were analyzed by SPSS 16 software and t-test. The frequency of CYP3A4*1B/*1B, CYP3A4*1B/*1A, CYP3A4*1B/*1C, and CYP3A4*1A/*1C was 67.35%, 10.64%, 19.12% and 2.89%, respectively. According to our results, CYP3A4 *1B/*1B genotype was the most common, and patients with CYP3A4*1B/*1B alleles needed a higher daily dose of rivaroxaban than *1B/*1A, *1B/*1C, and *1A/*1C carriers (9.57 ± 1.54 mg/day, P=0.015). Therefore, according to the results, CYP3A4 gene polymorphism has an important effect on the dose of rivaroxaban required to maintain the International Normalized Ratio (INR) in the range of 2-3.
Selected author of this article by journal
This article is licensed under a CC BY License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit: http://creativecommons.org/licenses/by/4.0/
CMBR journal remains neutral with regard to jurisdictional claims in published maps and institutional afflictions.
Letters to Editor
Given that CMBR Journal's policy in accepting articles will be strict and will do its best to ensure that in addition to having the highest quality published articles, the published articles should have the least similarity (maximum 15%). Also, all the figures and tables in the article must be original and the copyright permission of images must be prepared by authors. However, some articles may have flaws and have passed the journal filter, which dear authors may find fault with. Therefore, the editor of the journal asks the authors, if they see an error in the published articles of the journal, to email the article information along with the documents to the journal office.
CMBR Journal welcomes letters to the editor ([email protected], [email protected]) for the post-publication discussions and corrections which allows debate post publication on its site, through the Letters to Editor. Critical letters can be sent to the journal editor as soon as the article is online. Following points are to be considering before sending the letters (comments) to the editor.
 Letters that include statements of statistics, facts, research, or theories should include appropriate references, although more than three are discouraged.
 Letters that are personal attacks on an author rather than thoughtful criticism of the author’s ideas will not be considered for publication.
 There is no limit to the number of words in a letter.
 Letter writers should include a statement at the beginning of the letter stating that it is being submitted either for publication or not.
 Anonymous letters will not be considered.
 Letter writers must include Name, Email Address, Affiliation, mobile phone number, and Comments.
 Letters will be answered as soon as possible.
- Mueck W, Lensing AW, Agnelli G, Decousus H, Prandoni P, Misselwitz F (2011) Rivaroxaban. Clinical pharmacokinetics 50:675-686. doi:http://doi.org/10.2165/11595320-000000000-00000
- De Vriese AS, Caluwé R, Van Der Meersch H, De Boeck K, De Bacquer D (2021) Safety and efficacy of vitamin K antagonists versus rivaroxaban in hemodialysis patients with atrial fibrillation: a multicenter randomized controlled trial. Journal of the American Society of Nephrology 32:1474-1483. doi:http://doi.org/10.1681/ASN.2020111566
- Rymer JA, Webb L, McCall D, Hills MT, Wang TY (2021) Differences in Preferences Between Clinicians and Patients for the Use and Dosing of Direct Oral Anticoagulants for Atrial Fibrillation. Journal of the American Heart Association 10:e020697. doi:http://doi.org/10.1161/JAHA.120.020697
- Fernández MS, Marín F, Rafols C, Arribas F, Barrios V, Cosín-Sales J, Sánchez MA (2021) Thromboembolic and bleeding events with rivaroxaban in clinical practice in Spain: impact of inappropriate doses (the EMIR study). Journal of Comparative Effectiveness Research 10:583-593. doi:http://doi.org/10.2217/cer-2020-0286
- Kreutz R, Mantovani LG, Haas S, Monje D, Schneider J, Bugge J-P, Gebel M, Tamm M, Ageno W, Turpie AG (2019) XALIA-LEA: An observational study of venous thromboembolism treatment with rivaroxaban and standard anticoagulation in the Asia-Pacific, Eastern Europe, the Middle East, Africa and Latin America. Thrombosis research 176:125-132. doi:http://doi.org/10.1016/j.thromres.2019.02.010
- Eerenberg E, Middeldorp S, Levi M, Lensing A, Büller H (2015) Clinical impact and course of major bleeding with rivaroxaban and vitamin K antagonists. Journal of Thrombosis and Haemostasis 13:1590-1596. doi:http://doi.org/10.1111/jth.13051
- Siegal DM, Konkle BA (2014) What is the effect of rivaroxaban on routine coagulation tests? Hematology 2014, the American Society of Hematology Education Program Book 2014:334-336. doi:http://doi.org/10.1182/asheducation-2014.1.334
- Tsai HON, Goh JJN, Aw JWX, Lin Y, Fong AYY, Tiong LL, Tan DS-Y (2018) Comparison of rivaroxaban concentrations between Asians and Caucasians and their correlation with PT/INR. Journal of thrombosis and thrombolysis 46:541-548. doi:https://doi.org/10.1007/s11239-018-1726-y
- Samama MM, Contant G, Spiro TE, Perzborn E, Le Flem L, Guinet C, Gourmelin Y, Rohde G, Martinoli J-L (2013) Laboratory assessment of rivaroxaban: a review. Thrombosis journal 11:1-7. doi:https://doi.org/10.1186/1477-9560-11-11
- Rathbun S, Tafur A, Grant R, Esmon N, Mauer K, Marlar RA (2015) Comparison of methods to determine rivaroxaban anti-factor Xa activity. Thrombosis research 135:394-397. doi:https://doi.org/10.1016/j.thromres.2014.11.017
- Robert J, Le Morvan V, Smith D, Pourquier P, Bonnet J (2005) Predicting drug response and toxicity based on gene polymorphisms. Critical reviews in oncology/hematology 54:171-196. doi:https://doi.org/10.1016/j.critrevonc.2005.01.005
- Rocha V, Porcher R, Fernandes J, Filion A, Bittencourt H, Silva W, Vilela G, Zanette D, Ferry C, Larghero J (2009) Association of drug metabolism gene polymorphisms with toxicities, graft-versus-host disease and survival after HLA-identical sibling hematopoietic stem cell transplantation for patients with leukemia. Leukemia 23:545-556. doi:https://doi.org/10.1038/leu.2008.323
- Prabhune SS, Dighe V, Pradhan NS (2015) Enantiomeric separation of rivaroxaban by a chiral liquid chromatographic method. International Journal of Pharmacy and Pharmaceutical Sciences 7:399-402
- Wong C-K, White HD (2013) Rivaroxaban for the treatment of acute coronary syndromes. Expert opinion on pharmacotherapy 14:917-927. doi:https://doi.org/10.1517/14656566.2013.780029
- Straub A, Roehrig S, Hillisch A (2010) Entering the era of non-basic P1 site groups: discovery of Xarelto™(Rivaroxaban). Current topics in medicinal chemistry 10:257-269. doi:https://doi.org/10.2174/156802610790725506
- Werk AN, Cascorbi I (2014) Functional gene variants of CYP3A4. Clinical Pharmacology & Therapeutics 96:340-348. doi:https://doi.org/10.1038/clpt.2014.129
- Gnerre C, Blättler S, Kaufmann MR, Looser R, Meyer UA (2004) Regulation of CYP3A4 by the bile acid receptor FXR: evidence for functional binding sites in the CYP3A4 gene. Pharmacogenetics and Genomics 14:635-645. doi:https://doi.org/10.1124/dmd.114.062836
- García‐Martín E, Martínez C, Pizarro RM, García‐Gamito FJ, Gullsten H, Raunio H, Agúndez JA (2002) CYP3A4 variant alleles in white individuals with low CYP3A4 enzyme activity. Clinical pharmacology & therapeutics 71:196-204. doi:https://doi.org/10.1067/mcp.2002.121371
- Li AP, Kaminski DL, Rasmussen A (1995) Substrates of human hepatic cytochrome P450 3A4. Toxicology 104:1-8. doi:https://doi.org/10.1016/0300-483X(95)03155-9
- Drabina P, Feixová V, Sedlák M (2019) New synthetic strategy for preparation of the anticoagulant drug Rivaroxaban via an asymmetric Henry reaction. Tetrahedron Letters 60:99-101. doi:https://doi.org/10.1016/j.tetlet.2018.11.067
- Hesselink DA, van Schaik RH, Van Der Heiden IP, van der Werf M, Gregoor PJS, Lindemans J, Weimar W, van Gelder T (2003) Genetic polymorphisms of the CYP3A4, CYP3A5, and MDR‐1 genes and pharmacokinetics of the calcineurin inhibitors cyclosporine and tacrolimus. Clinical Pharmacology & Therapeutics 74:245-254. doi:https://doi.org/10.1016/S0009-9236(03)00168-1
- Matsumura K, Saito T, Takahashi Y, Ozeki T, Kiyotani K, Fujieda M, Yamazaki H, Kunitoh H, Kamataki T (2004) Identification of a novel polymorphic enhancer of the human CYP3A4 gene. Molecular pharmacology 65:326-334. doi:https://doi.org/10.1124/mol.65.2.326
- Klein K, Thomas M, Winter S, Nussler AK, Niemi M, Schwab M, Zanger UM (2012) PPARA: a novel genetic determinant of CYP3A4 in vitro and in vivo. Clinical Pharmacology & Therapeutics 91:1044-1052. doi:https://doi.org/10.1038/clpt.2011.336
- Rodríguez-Antona C, Sayi JG, Gustafsson LL, Bertilsson L, Ingelman-Sundberg M (2005) Phenotype–genotype variability in the human CYP3A locus as assessed by the probe drug quinine and analyses of variant CYP3A4 alleles. Biochemical and biophysical research communications 338:299-305. doi:https://doi.org/10.1016/j.bbrc.2005.09.020
- Gellner K, Eiselt R, Hustert E, Arnold H, Koch I, Haberl M, Deglmann CJ, Burk O, Buntefuss D, Escher S (2001) Genomic organization of the human CYP3A locus: identification of a new, inducible CYP3A gene. Pharmacogenetics and Genomics 11:111-121. doi:https://doi.org/10.1097/00008571-200103000-00002
- Bruckmueller H, Werk AN, Renders L, Feldkamp T, Tepel M, Borst C, Caliebe A, Kunzendorf U, Cascorbi I (2015) Which genetic determinants should be considered for tacrolimus dose optimization in kidney transplantation? A combined analysis of genes affecting the CYP3A locus. Therapeutic drug monitoring 37:288-295. doi:https://doi.org/10.1097/FTD.0000000000000142
- Falzoi M, Mossa A, Congeddu E, Saba L, Pani L (2010) Multiplex genotyping of CYP3A4, CYP3A5, CYP2C9 and CYP2C19 SNPs using MALDI-TOF mass spectrometry. Pharmacogenomics 11:559-571. doi:https://doi.org/10.2217/pgs.09.172
- Kubitza D, Becka M, Zuehlsdorf M, Mueck W (2007) Body weight has limited influence on the safety, tolerability, pharmacokinetics, or pharmacodynamics of rivaroxaban (BAY 59‐7939) in healthy subjects. The Journal of Clinical Pharmacology 47:218-226. doi:https://doi.org/10.1177/0091270006296058
- Lorenzini K, Daali Y, Fontana P, Desmeules J, Samer C (2016) Rivaroxaban-induced hemorrhage associated with ABCB1 genetic defect. Frontiers in pharmacology 7:494. doi:https://doi.org/10.3389/fphar.2016.00494/full
- Gouin‐Thibault I, Delavenne X, Blanchard A, Siguret V, Salem J, Narjoz C, Gaussem P, Beaune P, Funck‐Brentano C, Azizi M (2017) Interindividual variability in dabigatran and rivaroxaban exposure: contribution of ABCB 1 genetic polymorphisms and interaction with clarithromycin. Journal of Thrombosis and Haemostasis 15:273-283. doi:https://doi.org/doi.org/10.1111/jth.13577
- Nakagawa J, Kinjo T, Iizuka M, Ueno K, Tomita H, Niioka T (2021) Impact of gene polymorphisms in drug‐metabolizing enzymes and transporters on trough concentrations of rivaroxaban in patients with atrial fibrillation. Basic & Clinical Pharmacology & Toxicology 128:297-304. doi:https://doi.org/10.1111/bcpt.13488
- Sychev D, Minnigulov R, Bochkov P, Ryzhikova K, Yudina I, Lychagin A, Morozova T (2019) Effect of CYP3A4, CYP3A5, ABCB1 gene polymorphisms on rivaroxaban pharmacokinetics in patients undergoing total hip and knee replacement surgery. High Blood Pressure & Cardiovascular Prevention 26:413-420. doi:https://doi.org/10.1007/s40292-019-00342-4
- Hsieh K-P, Lin Y-Y, Cheng C-L, Lai M-L, Lin M-S, Siest J-P, Huang J-D (2001) Novel mutations of CYP3A4 in Chinese. Drug metabolism and disposition 29:268-273
- Wojakowski E, Cheruvil C, Hassan A, Holsen M, Chen L, Rossi M, Wilcox N, Woodruff A (2020) Albumin and bleed risk in rivaroxaban treated patients. Journal of thrombosis and thrombolysis 50:1004-1011. doi:https://doi.org/10.1007/s11239-020-02092-w
- Escolar G, Carne X, Arellano-Rodrigo E (2015) Dosing of rivaroxaban by indication: getting the right dose for the patient. Expert opinion on drug metabolism & toxicology 11:1665-1677. doi:https://doi.org/10.1517/17425255.2015.1085022
- De Vriese AS, Caluwé R, Bailleul E, De Bacquer D, Borrey D, Van Vlem B, Vandecasteele SJ, Emmerechts J (2015) Dose-finding study of rivaroxaban in hemodialysis patients. American Journal of Kidney Diseases 66:91-98. doi:https://doi.org/10.1053/j.ajkd.2015.01.022
- Ashida R, Okamura Y, Ohshima K, Kakuda Y, Uesaka K, Sugiura T, Ito T, Yamamoto Y, Sugino T, Urakami K (2017) CYP3A4 gene is a novel biomarker for predicting a poor prognosis in hepatocellular carcinoma. Cancer genomics & proteomics 14:445-453. doi:https://doi.org/10.21873/cgp.20054
- Hole K, Wollmann BM, Nguyen C, Haslemo T, Molden E (2018) Comparison of CYP3A4-inducing capacity of enzyme-inducing antiepileptic drugs using 4β-hydroxycholesterol as biomarker. Therapeutic drug monitoring 40:463-468. doi:https://doi.org/10.1097/FTD.0000000000000518
- Lv J, Liu F, Feng N, Sun X, Tang J, Xie L, Wang Y (2018) CYP3A4 gene polymorphism is correlated with individual consumption of sufentanil. Acta Anaesthesiologica Scandinavica 62:1367-1373. doi:https://doi.org/10.1111/aas.13178
- Yamamoto T, Nagafuchi N, Ozeki T, Kubota T, Ishikawa H, Ogawa S, Yamada Y, Hirai H, Iga T (2003) CYP3A4* 18: it is not rare allele in Japanese population. Drug metabolism and pharmacokinetics 18:267-268. doi:https://doi.org/10.2133/dmpk.18.267