{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T22:34:30Z","timestamp":1781735670666,"version":"3.54.5"},"reference-count":32,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T00:00:00Z","timestamp":1760054400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012190","name":"Ministry of Science and Higher Education of the Russian Federation","doi-asserted-by":"crossref","award":["075-15-2025-463"],"award-info":[{"award-number":["075-15-2025-463"]}],"id":[{"id":"10.13039\/501100012190","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is associated with a fivefold increase in stroke risk. Direct oral anticoagulants (DOACs), including apixaban, are now the preferred therapy for stroke prevention in patients with non-valvular AF (NVAF). However, interindividual variability in drug response and safety remains a major challenge, particularly in elderly patients with comorbidities and polypharmacy. Genetic polymorphisms in drug-metabolizing enzymes and transporters may contribute to variability in apixaban exposure and bleeding risk. This study aimed to evaluate the association of polymorphisms in ABCB1, CYP3A4, and CYP3A5 with steady-state plasma concentrations of apixaban (Cssmin) and hemorrhagic complications in elderly patients with NVAF. Methods: This cross-sectional study included 197 patients (mean age 83 \u00b1 8 years; 67% women) with NVAF treated with apixaban (5 mg twice daily). Genotyping of ABCB1 (rs1045642, rs2032582, rs1128503), CYP3A4*22 (rs35599367), and CYP3A5*3 (rs776746) was performed using allele-specific real-time PCR. Cssmin of apixaban was determined by high-performance liquid chromatography coupled with tandem mass spectrometry. Associations with bleeding events were evaluated. Results: Bleeding events were recorded in 40 patients (20.3%). An association signal was observed for ABCB1 rs1045642, where carriers of the CC genotype had a higher risk of bleeding compared with alternative alleles (OR = 2.805; 95% CI: 1.326\u20135.935; p = 0.006). After correction for multiple testing, the association remained significant only under the log-additive model (OR = 1.93 per C allele; 95% CI: 1.17\u20133.20; q = 0.0275; p_adj = 0.044), while recessive and codominant effects did not withstand Bonferroni adjustment. No significant associations were observed for rs2032582, rs1128503, CYP3A4*22, or CYP3A5*3. None of the studied polymorphisms, including rs1045642, significantly affected Cssmin. Concomitant therapy, particularly with antiarrhythmic drugs and statins (rosuvastatin), also increased bleeding risk. Conclusions: The findings highlight the potential contribution of ABCB1 rs1045642 and specific drug\u2013drug interactions to the risk of hemorrhagic complications in elderly NVAF patients receiving apixaban.<\/jats:p>","DOI":"10.3390\/genes16101179","type":"journal-article","created":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:50:16Z","timestamp":1760107816000},"page":"1179","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Impact of Xenobiotic Detoxification Gene Polymorphisms on Steady-State Plasma Concentrations of Apixaban and the Development of Hemorrhagic Complications in Older Patients with Non-Valvular Atrial Fibrillation"],"prefix":"10.3390","volume":"16","author":[{"given":"Andrey P.","family":"Kondrakhin","sequence":"first","affiliation":[{"name":"Moscow Healthcare Department, War Veterans Hospital No. 2, Moscow 109472, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9001-1499","authenticated-orcid":false,"given":"Sherzod P.","family":"Abdullaev","sequence":"additional","affiliation":[{"name":"Federal State Budgetary Research Institution \u00abRussian Research Center of Surgery Named After Academician B.V. Petrovsky\u00bb, Moscow 119991, Russia"},{"name":"Federal State Budgetary Educational Institution, Ministry of Healthcare of the Russian Federation, Further Professional Education \u201cRussian Medical Academy of Continuous Professional Education\u201d, Moscow 125993, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan V.","family":"Sychev","sequence":"additional","affiliation":[{"name":"Federal State Budgetary Research Institution \u00abRussian Research Center of Surgery Named After Academician B.V. Petrovsky\u00bb, Moscow 119991, Russia"},{"name":"Federal State Budgetary Educational Institution, Ministry of Healthcare of the Russian Federation, Further Professional Education \u201cRussian Medical Academy of Continuous Professional Education\u201d, Moscow 125993, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8555-5969","authenticated-orcid":false,"given":"Pavel O.","family":"Bochkov","sequence":"additional","affiliation":[{"name":"Federal State Budgetary Educational Institution, Ministry of Healthcare of the Russian Federation, Further Professional Education \u201cRussian Medical Academy of Continuous Professional Education\u201d, Moscow 125993, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-2744-2752","authenticated-orcid":false,"given":"Svetlana N.","family":"Tuchkova","sequence":"additional","affiliation":[{"name":"Federal State Budgetary Research Institution \u00abRussian Research Center of Surgery Named After Academician B.V. Petrovsky\u00bb, Moscow 119991, Russia"},{"name":"Federal State Budgetary Educational Institution, Ministry of Healthcare of the Russian Federation, Further Professional Education \u201cRussian Medical Academy of Continuous Professional Education\u201d, Moscow 125993, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin B.","family":"Mirzaev","sequence":"additional","affiliation":[{"name":"Federal State Budgetary Research Institution \u00abRussian Research Center of Surgery Named After Academician B.V. Petrovsky\u00bb, Moscow 119991, Russia"},{"name":"Federal State Budgetary Educational Institution, Ministry of Healthcare of the Russian Federation, Further Professional Education \u201cRussian Medical Academy of Continuous Professional Education\u201d, Moscow 125993, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maksim L.","family":"Maksimov","sequence":"additional","affiliation":[{"name":"Federal State Budgetary Educational Institution, Ministry of Healthcare of the Russian Federation, Further Professional Education \u201cRussian Medical Academy of Continuous Professional Education\u201d, Moscow 125993, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4496-3680","authenticated-orcid":false,"given":"Dmitry A.","family":"Sychev","sequence":"additional","affiliation":[{"name":"Federal State Budgetary Research Institution \u00abRussian Research Center of Surgery Named After Academician B.V. Petrovsky\u00bb, Moscow 119991, Russia"},{"name":"Federal State Budgetary Educational Institution, Ministry of Healthcare of the Russian Federation, Further Professional Education \u201cRussian Medical Academy of Continuous Professional Education\u201d, Moscow 125993, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2982","DOI":"10.1016\/j.jacc.2020.11.010","article-title":"Global Burden of Cardiovascular Diseases and Risk Factors, 1990\u20132019: Update from the GBD 2019 Study","volume":"76","author":"Roth","year":"2020","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Tang, J., Zhang, Q., Peng, S., Li, H., Hu, W., Hao, M., Liu, Y., Sun, M., Cao, W., and Yin, N. (2024). 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