{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T10:28:47Z","timestamp":1780568927187,"version":"3.54.1"},"reference-count":81,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,2,19]],"date-time":"2025-02-19T00:00:00Z","timestamp":1739923200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2025,2,19]],"date-time":"2025-02-19T00:00:00Z","timestamp":1739923200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"funder":[{"name":"European Union\u2019s Horizon 2020 research and innovation program","award":["860329 Marie-Curie ITN \u201cSTRATEGY-CKD"],"award-info":[{"award-number":["860329 Marie-Curie ITN \u201cSTRATEGY-CKD"]}]},{"name":"EU Horizon 2020 program Epic-XS","award":["0000432"],"award-info":[{"award-number":["0000432"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"DOI":"10.1038\/s41598-025-90405-5","type":"journal-article","created":{"date-parts":[[2025,2,19]],"date-time":"2025-02-19T10:32:31Z","timestamp":1739961151000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Unveiling the role of sex in the metabolism of indoxyl sulfate and apixaban"],"prefix":"10.1038","volume":"15","author":[{"given":"Blanca","family":"Pina-Beltran","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Dimitrov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"McKay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthieu","family":"Giot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zbyn\u011bk","family":"Zdr\u00e1hal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Pot\u011b\u0161il","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V\u00e1clav","family":"Pustka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge","family":"Peinado-Izaguerri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julio","family":"Saez-Rodriguez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"St\u00e9phane","family":"Poitevin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"St\u00e9phane","family":"Burtey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,2,19]]},"reference":[{"key":"90405_CR1","doi-asserted-by":"publisher","unstructured":"Kovesdy, C. P. Epidemiology of chronic kidney disease: an update 2022. Kidney Int. Suppl. 12(1), 7\u201311. https:\/\/doi.org\/10.1016\/j.kisu.2021.11.003 (2022).","DOI":"10.1016\/j.kisu.2021.11.003"},{"key":"90405_CR2","doi-asserted-by":"publisher","unstructured":"Sundstr\u00f6m, J. et al. Prevalence, outcomes, and cost of chronic kidney disease in a contemporary population of 2\u00b74 million patients from 11 countries: the CaReMe CKD study. Lancet Reg. Health Eur. 20, 89. https:\/\/doi.org\/10.1016\/j.lanepe.2022.100438 (2022).","DOI":"10.1016\/j.lanepe.2022.100438"},{"key":"90405_CR3","doi-asserted-by":"publisher","unstructured":"Ricardo, A. C. et al. Sex-related disparities in CKD progression. J. Am. Soc. Nephrol. 30(1), 137\u2013146. https:\/\/doi.org\/10.1681\/ASN.2018030296 (2019).","DOI":"10.1681\/ASN.2018030296"},{"key":"90405_CR4","doi-asserted-by":"publisher","unstructured":"Balafa, O. et al. Sex disparities in mortality and cardiovascular outcomes in chronic kidney disease. Clin. Kidney J.  17(3), sfae044.   https:\/\/doi.org\/10.1093\/ckj\/sfae044 (2024).","DOI":"10.1093\/ckj\/sfae044"},{"key":"90405_CR5","doi-asserted-by":"publisher","unstructured":"MacRae, C., Mercer, S. W., Guthrie, B. & Henderson, D. Comorbidity in chronic kidney disease: a large cross-sectional study of prevalence in Scottish primary care. Br. J. Gen. Pract. 71(704), e243\u2013e249. https:\/\/doi.org\/10.3399\/bjgp20X714125 (2021).","DOI":"10.3399\/bjgp20X714125"},{"key":"90405_CR6","doi-asserted-by":"publisher","unstructured":"Jankowski, J., Floege, J., Fliser, D., B\u00f6hm, M. & Marx, N. Cardiovascular disease in chronic kidney disease.  Circulation 143(11), 1157\u20131172. https:\/\/doi.org\/10.1161\/CIRCULATIONAHA.120.050686  (2021).","DOI":"10.1161\/CIRCULATIONAHA.120.050686"},{"key":"90405_CR7","doi-asserted-by":"publisher","unstructured":"Sall\u00e9e, M. et al. The aryl hydrocarbon receptor-activating effect of uremic toxins from tryptophan metabolism: a new concept to understand cardiovascular complications of chronic kidney disease. Toxins  6(3), 934\u2013949. https:\/\/doi.org\/10.3390\/toxins6030934  (2014).","DOI":"10.3390\/toxins6030934"},{"key":"90405_CR8","doi-asserted-by":"publisher","unstructured":"Nunns, G. R. et al. The hypercoagulability paradox of chronic kidney disease: the role of fibrinogen. Am. J. Surg. 214(6), 1215\u20131218.  https:\/\/doi.org\/10.1016\/j.amjsurg.2017.08.039 (2017).","DOI":"10.1016\/j.amjsurg.2017.08.039"},{"key":"90405_CR9","doi-asserted-by":"publisher","unstructured":"Lutz, J., Menke, J., Sollinger, D., Schinzel, H. & Th\u00fcrmel, K. Haemostasis in chronic kidney disease. Nephrol. Dial. Transplant. 29(1), 29\u201340. https:\/\/doi.org\/10.1093\/ndt\/gft209  (2014).","DOI":"10.1093\/ndt\/gft209"},{"key":"90405_CR10","doi-asserted-by":"publisher","unstructured":"Addi, T., Dou, L. & Burtey, S. Tryptophan-derived uremic toxins and thrombosis in chronic kidney disease. Toxins 10(10), 10. https:\/\/doi.org\/10.3390\/toxins10100412  (2018).","DOI":"10.3390\/toxins10100412"},{"key":"90405_CR11","doi-asserted-by":"publisher","unstructured":"Gadde, S. et al. Atrial fibrillation in chronic kidney disease: an overview. Cureus 14(8), e27753. https:\/\/doi.org\/10.7759\/cureus.27753 (2023).","DOI":"10.7759\/cureus.27753"},{"key":"90405_CR12","doi-asserted-by":"publisher","unstructured":"Folsom, A. R. et al. Chronic kidney disease and venous thromboembolism: a prospective study. Nephrol. Dial. Transplant. Off. Publ. Eur. Dial. Transpl. Assoc. 25(10), 3296\u20133301. https:\/\/doi.org\/10.1093\/ndt\/gfq179  (2010).","DOI":"10.1093\/ndt\/gfq179"},{"key":"90405_CR13","doi-asserted-by":"publisher","unstructured":"Yu, W. Y. H. et al. Warfarin-associated nonuremic calciphylaxis. JAMA Dermatol. 153(3), 309\u2013314. https:\/\/doi.org\/10.1001\/jamadermatol.2016.4821 (2017).","DOI":"10.1001\/jamadermatol.2016.4821"},{"key":"90405_CR14","doi-asserted-by":"publisher","unstructured":"Hammett, C. et al. Oral anticoagulant use in patients with atrial fibrillation and chronic kidney disease: a review of the evidence with recommendations for Australian Clinical Practice. Heart Lung Circ. 31(12), 1604\u20131611. https:\/\/doi.org\/10.1016\/j.hlc.2022.09.003   (2022).","DOI":"10.1016\/j.hlc.2022.09.003"},{"key":"90405_CR15","doi-asserted-by":"publisher","unstructured":"Wetmore, J. B. et al. Apixaban dosing patterns Versus Warfarin in patients with Nonvalvular Atrial Fibrillation receiving Dialysis: a retrospective cohort study. Am. J. Kidney Dis. https:\/\/doi.org\/10.1053\/j.ajkd.2022.03.007 (2022).","DOI":"10.1053\/j.ajkd.2022.03.007"},{"issue":"10","key":"90405_CR16","doi-asserted-by":"publisher","first-page":"1265","DOI":"10.1007\/s40262-019-00775-z","volume":"58","author":"W Byon","year":"2019","unstructured":"Byon, W., Garonzik, S., Boyd, R. A. & Frost, C. E. Apixaban: a clinical pharmacokinetic and pharmacodynamic review. Clin. Pharmacokinet. 58(10), 1265\u20131279. https:\/\/doi.org\/10.1007\/s40262-019-00775-z (2019).","journal-title":"Clin. Pharmacokinet."},{"key":"90405_CR17","doi-asserted-by":"publisher","unstructured":"Fatima, H. et al. Safety and efficacy of apixaban vs warfarin in patients with stage 4 and 5 chronic kidney disease: a systematic review. Cureus J. Med. Sci. 14,  10. https:\/\/doi.org\/10.7759\/cureus.30230  (2022).","DOI":"10.7759\/cureus.30230"},{"key":"90405_CR18","doi-asserted-by":"publisher","unstructured":"Parker, K. et al. A systematic review of the efficacy and safety of anticoagulants in advanced chronic kidney disease. J. Nephrol. 35(8), 2015\u20132033. https:\/\/doi.org\/10.1007\/s40620-022-01413-x   (2022).","DOI":"10.1007\/s40620-022-01413-x"},{"key":"90405_CR19","doi-asserted-by":"publisher","unstructured":"Vondracek, S. F., Teitelbaum, I. & Kiser, T. H. Principles of kidney pharmacotherapy for the nephrologist: core curriculum 2021. Am. J. Kidney Dis.  78(3), 442\u2013458. https:\/\/doi.org\/10.1053\/j.ajkd.2021.02.342   (2021).","DOI":"10.1053\/j.ajkd.2021.02.342"},{"key":"90405_CR20","doi-asserted-by":"publisher","unstructured":"Santana Machado, T., Cerini, C. & Burtey, S. Emerging roles of aryl hydrocarbon receptors in the altered clearance of drugs during chronic kidney disease. Toxins  11(4),  E209. https:\/\/doi.org\/10.3390\/toxins11040209   (2019).","DOI":"10.3390\/toxins11040209"},{"key":"90405_CR21","doi-asserted-by":"publisher","unstructured":"Fujii-Kuriyama, Y. & Mimura, J. Molecular mechanisms of AhR functions in the regulation of cytochrome P450 genes. Biochem. Biophys. Res. Commun.  338(1),  311\u2013317. https:\/\/doi.org\/10.1016\/j.bbrc.2005.08.162   (2005).","DOI":"10.1016\/j.bbrc.2005.08.162"},{"key":"90405_CR22","doi-asserted-by":"publisher","unstructured":"Gondouin, B. et al. Indolic uremic solutes increase tissue factor production in endothelial cells by the aryl hydrocarbon receptor pathway.  Kidney Int. 84(4),  733\u2013744.  https:\/\/doi.org\/10.1038\/ki.2013.133   (2013).","DOI":"10.1038\/ki.2013.133"},{"issue":"4","key":"90405_CR23","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1007\/BF03226377","volume":"26","author":"E Banoglu","year":"2001","unstructured":"Banoglu, E., Jha, G. G. & King, R. S. Hepatic microsomal metabolism of indole to indoxyl, a precursor of indoxyl sulfate. Eur. J. Drug Metab. Pharmacokinet. 26(4), 235\u2013240 (2001).","journal-title":"Eur. J. Drug Metab. Pharmacokinet."},{"key":"90405_CR24","doi-asserted-by":"publisher","unstructured":"Banoglu, E. & King, R. S. Sulfation of indoxyl by human and rat aryl (phenol) sulfotransferases to form indoxyl sulfate. Eur. J. Drug Metab. Pharmacokinet.  27(2), 135\u2013140. https:\/\/doi.org\/10.1007\/BF03190428   (2002).","DOI":"10.1007\/BF03190428"},{"key":"90405_CR25","doi-asserted-by":"publisher","unstructured":"Ma, Q., Zhang, X. & Qu, Y. Biodegradation and biotransformation of indole: advances and perspectives.  Front. Microbiol.  9,12.  https:\/\/www.frontiersin.org\/articles\/, https:\/\/doi.org\/10.3389\/fmicb.2018.02625  (2018).","DOI":"10.3389\/fmicb.2018.02625"},{"key":"90405_CR26","doi-asserted-by":"publisher","unstructured":"Niwa, T. Indoxyl sulfate is a nephro-vascular toxin. J. Ren. Nutr. 20(5), S2\u2013S6. https:\/\/doi.org\/10.1053\/j.jrn.2010.05.002 (2010).","DOI":"10.1053\/j.jrn.2010.05.002"},{"key":"90405_CR27","doi-asserted-by":"publisher","unstructured":"Kami\u0144ski, T. W., Pawlak, K., Karbowska, M., My\u015bliwiec, M. & Pawlak, D. Indoxyl sulfate\u2014the uremic toxin linking hemostatic system disturbances with the prevalence of cardiovascular disease in patients with chronic kidney disease. BMC Nephrol. 18(1), 35. https:\/\/doi.org\/10.1186\/s12882-017-0457-1 (2017).","DOI":"10.1186\/s12882-017-0457-1"},{"key":"90405_CR28","doi-asserted-by":"publisher","unstructured":"Lano, G., Burtey, S. & Sall\u00e9e, M. Indoxyl sulfate, a uremic endotheliotoxin. Toxins  12(4),  4. https:\/\/doi.org\/10.3390\/toxins12040229  (2020).","DOI":"10.3390\/toxins12040229"},{"key":"90405_CR29","doi-asserted-by":"publisher","unstructured":"Santana Machado, T. et al. Indoxyl sulfate upregulates liver P-glycoprotein expression and activity through aryl hydrocarbon receptor signaling. J. Am. Soc. Nephrol. JASN  29(3),  906\u2013918.  https:\/\/doi.org\/10.1681\/ASN.2017030361   (2018).","DOI":"10.1681\/ASN.2017030361"},{"key":"90405_CR30","doi-asserted-by":"publisher","unstructured":"Dreisbach, A. W. & Lertora, J. J. The effect of chronic renal failure on drug metabolism and transport. Expert Opin. Drug Metab. Toxicol. 4(8), 1065\u20131074. https:\/\/doi.org\/10.1517\/17425255.4.8.1065  (2008).","DOI":"10.1517\/17425255.4.8.1065"},{"key":"90405_CR31","doi-asserted-by":"publisher","unstructured":"Schmidt, J. V., Su, G. H., Reddy, J. K., Simon, M. C. & Bradfield, C. A. Characterization of a murine Ahr null allele: involvement of the Ah receptor in hepatic growth and development. Proc. Natl. Acad. Sci.  93(13),  6731\u20136736.  https:\/\/doi.org\/10.1073\/pnas.93.13.6731   (1996).","DOI":"10.1073\/pnas.93.13.6731"},{"key":"90405_CR32","doi-asserted-by":"publisher","unstructured":"du Sert, N. P. et al. Reporting animal research: explanation and elaboration for the ARRIVE guidelines 2.0. PLOS Biol.  18(7), e3000411. https:\/\/doi.org\/10.1371\/journal.pbio.3000411   (2020).","DOI":"10.1371\/journal.pbio.3000411"},{"key":"90405_CR33","doi-asserted-by":"publisher","unstructured":"Calaf, R. et al. Determination of uremic solutes in biological fluids of chronic kidney disease patients by HPLC assay. J. Chromatogr. B Analyt. Technol. Biomed. Life. Sci. 879(23), 2281\u20132286. https:\/\/doi.org\/10.1016\/j.jchromb.2011.06.014 (2011).","DOI":"10.1016\/j.jchromb.2011.06.014"},{"key":"90405_CR34","unstructured":"\u2018Willekens et al.  A universal anti-Xa assay for rivaroxaban, apixaba.pdf. (2021, accessed 24 Jun 2024).  https:\/\/zlmsg.ch\/wp-content\/uploads\/2021\/05\/2021-Br-J-Haematol_Willekens.pdf."},{"key":"90405_CR35","doi-asserted-by":"publisher","unstructured":"Livak, K. J. & Schmittgen, T. D. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods San Diego Calif  25(4), 402\u2013408. https:\/\/doi.org\/10.1006\/meth.2001.1262   (2001).","DOI":"10.1006\/meth.2001.1262"},{"issue":"5","key":"90405_CR36","doi-asserted-by":"publisher","first-page":"1149","DOI":"10.1111\/j.1582-4934.2007.00090.x","volume":"11","author":"DM Smadja","year":"2007","unstructured":"Smadja, D. M. et al. Increased VEGFR2 expression during human late endothelial progenitor cells expansion enhances in vitro angiogenesis with up-regulation of integrin alpha(6). J. Cell. Mol. Med. 11(5), 1149\u20131161. https:\/\/doi.org\/10.1111\/j.1582-4934.2007.00090.x (2007).","journal-title":"J. Cell. Mol. Med."},{"key":"90405_CR37","doi-asserted-by":"publisher","unstructured":"T\u00fcrei, D., Korcsm\u00e1ros, T. & Saez-Rodriguez, J. OmniPath: guidelines and gateway for literature-curated signaling pathway resources.  Nat. Methods 13(12), 966\u2013967.  https:\/\/doi.org\/10.1038\/nmeth.4077   (2016).","DOI":"10.1038\/nmeth.4077"},{"key":"90405_CR38","doi-asserted-by":"publisher","unstructured":"V\u00e4likangas, T., Suomi, T. & Elo, L. L. A systematic evaluation of normalization methods in quantitative label-free proteomics. Brief. Bioinform. 19(1), 1\u201311. https:\/\/doi.org\/10.1093\/bib\/bbw095 (2016).","DOI":"10.1093\/bib\/bbw095"},{"key":"90405_CR39","doi-asserted-by":"publisher","unstructured":"Phipson, B. et al. Robust hyperparameter estimation protects against hypervariable genes and improves power to detect differential expression. Ann. Appl. Stat.  10(2),  946\u2013963.  https:\/\/doi.org\/10.1214\/16-AOAS920  (2016).","DOI":"10.1214\/16-AOAS920"},{"key":"90405_CR40","doi-asserted-by":"publisher","unstructured":"Badia-i-Mompel, P. et al. DecoupleR: ensemble of computational methods to infer biological activities from omics data. Bioinforma Adv. 2(1), vbac016. https:\/\/doi.org\/10.1093\/bioadv\/vbac016 (2022).","DOI":"10.1093\/bioadv\/vbac016"},{"key":"90405_CR41","doi-asserted-by":"publisher","unstructured":"Liberzon, A. et al. The Molecular Signatures Database (MSigDB) hallmark gene set collection. Cell Syst.  1(6), 417\u2013425. https:\/\/doi.org\/10.1016\/j.cels.2015.12.004   (2015).","DOI":"10.1016\/j.cels.2015.12.004"},{"key":"90405_CR42","doi-asserted-by":"publisher","unstructured":"Jansen, J. et al. Remote sensing and signaling in kidney proximal tubules stimulates gut microbiome-derived organic anion secretion.  Proc. Natl. Acad. Sci. 116(32), 16105\u201316110. https:\/\/doi.org\/10.1073\/pnas.1821809116   (2019).","DOI":"10.1073\/pnas.1821809116"},{"key":"90405_CR43","doi-asserted-by":"publisher","unstructured":"K\u00f6nig, C. et al. Thirty mouse strain survey of voluntary physical activity and energy expenditure: influence of strain, sex and day\u2013night variation. Front. Neurosci. 14, 896.  https:\/\/doi.org\/10.3389\/fnins.2020.00531 (2020).","DOI":"10.3389\/fnins.2020.00531"},{"key":"90405_CR44","doi-asserted-by":"publisher","unstructured":"Hylek, E. M. Apixaban for end-stage kidney disease.  Circulation 138(15), 1534\u20131536.  https:\/\/doi.org\/10.1161\/CIRCULATIONAHA.118.036449  (2018).","DOI":"10.1161\/CIRCULATIONAHA.118.036449"},{"key":"90405_CR45","doi-asserted-by":"publisher","unstructured":"Zhang, D. et al. Comparative metabolism of 14\u00a0C-labeled apixaban in mice, rats, rabbits, dogs, and humans. Drug Metab. Dispos. Biol. Fate Chem. 37(8), 1738\u20131748. https:\/\/doi.org\/10.1124\/dmd.108.025981 (2009).","DOI":"10.1124\/dmd.108.025981"},{"key":"90405_CR46","doi-asserted-by":"publisher","unstructured":"Bushi, D. et al. Apixaban decreases brain thrombin activity in a male mouse model of acute ischemic stroke.  J. Neurosci. Res.  96(8), 1406\u20131411. https:\/\/doi.org\/10.1002\/jnr.24253  (2018).","DOI":"10.1002\/jnr.24253"},{"key":"90405_CR47","doi-asserted-by":"publisher","unstructured":"Beery, A. K. Inclusion of females does not increase variability in rodent research studies. Curr. Opin. Behav. Sci. 23, 143\u2013149. https:\/\/doi.org\/10.1016\/j.cobeha.2018.06.016 (2018).","DOI":"10.1016\/j.cobeha.2018.06.016"},{"key":"90405_CR48","doi-asserted-by":"publisher","unstructured":"Bierer, B. E., Meloney, L. G., Ahmed, H. R. & White, S. A. Advancing the inclusion of underrepresented women in clinical research. Cell. Rep. Med. 3(4), 100553. https:\/\/doi.org\/10.1016\/j.xcrm.2022.100553 (2022).","DOI":"10.1016\/j.xcrm.2022.100553"},{"key":"90405_CR49","doi-asserted-by":"publisher","unstructured":"Alahamadi, Z. et al. Race, sex, and kidney disease trial participation. Kidney Med. 5, 3. https:\/\/doi.org\/10.1016\/j.xkme.2022.100594 (2023).","DOI":"10.1016\/j.xkme.2022.100594"},{"key":"90405_CR50","doi-asserted-by":"publisher","unstructured":"Heerspink Hiddo, J. L. et al. Dapagliflozin in patients with chronic kidney disease. N. Engl. J. Med.  383(15), 1436\u20131446 https:\/\/doi.org\/10.1056\/NEJMoa2024816   (2020).","DOI":"10.1056\/NEJMoa2024816"},{"key":"90405_CR51","doi-asserted-by":"publisher","unstructured":"Vinson, A. J., Collister, D., Ahmed, S. & Tennankore, K. Underrepresentation of women in recent landmark kidney trials: the gender gap prevails. Kidney Int. Rep.  7(11),  2526\u20132529. https:\/\/doi.org\/10.1016\/j.ekir.2022.08.022  (2022).","DOI":"10.1016\/j.ekir.2022.08.022"},{"issue":"11","key":"90405_CR52","doi-asserted-by":"publisher","first-page":"981","DOI":"10.1056\/NEJMoa1107039","volume":"365","author":"B Granger Christopher","year":"2011","unstructured":"Granger Christopher, B. et al. Apixaban versus warfarin in patients with atrial fibrillation. N. Engl. J. Med. 365(11), 981\u2013992. https:\/\/doi.org\/10.1056\/NEJMoa1107039 (2011).","journal-title":"N. Engl. J. Med."},{"key":"90405_CR53","doi-asserted-by":"publisher","unstructured":"Santema, B. T. et al. Identifying optimal doses of heart failure medications in men compared with women: a prospective, observational, cohort study\u2019, The Lancet 394(10205), 1254\u20131263.  https:\/\/doi.org\/10.1016\/S0140-6736(19)31792-1  (2019).","DOI":"10.1016\/S0140-6736(19)31792-1"},{"key":"90405_CR54","doi-asserted-by":"publisher","unstructured":"Nolin, T. D. A synopsis of clinical pharmacokinetic alterations in advanced CKD. Semin. Dial. 28(4), 325\u2013329. https:\/\/doi.org\/10.1111\/sdi.12374   (2015).","DOI":"10.1111\/sdi.12374"},{"key":"90405_CR55","doi-asserted-by":"publisher","unstructured":"Jalal, D., Chonchol, M. & Targher, G. Disorders of hemostasis associated with chronic kidney disease. Semin. Thromb. Hemost.  36(1), 034\u2013040.  https:\/\/doi.org\/10.1055\/s-0030-1248722  (2010).","DOI":"10.1055\/s-0030-1248722"},{"key":"90405_CR56","doi-asserted-by":"publisher","unstructured":"Dou, L. et al. Aryl hydrocarbon receptor is activated in patients and mice with chronic kidney disease. Kidney Int. 93(4), 986\u2013999. https:\/\/doi.org\/10.1016\/j.kint.2017.11.010 (2018).","DOI":"10.1016\/j.kint.2017.11.010"},{"key":"90405_CR57","doi-asserted-by":"publisher","unstructured":"Frost, C. E. et al. Effects of age and sex on the single-dose pharmacokinetics and pharmacodynamics of apixaban. Clin. Pharmacokinet.  54(6), 651\u2013662. https:\/\/doi.org\/10.1007\/s40262-014-0228-0  (2015).","DOI":"10.1007\/s40262-014-0228-0"},{"key":"90405_CR58","doi-asserted-by":"publisher","unstructured":"Zhang, D. et al. Characterization of efflux transporters involved in distribution and disposition of apixaban.  Drug Metab. Dispos. Biol. Fate Chem.  41(4), 827\u2013835. https:\/\/doi.org\/10.1124\/dmd.112.050260   (2013).","DOI":"10.1124\/dmd.112.050260"},{"key":"90405_CR59","doi-asserted-by":"publisher","unstructured":"Kim, H. et al. ABCG2 gene polymorphisms may affect the bleeding risk in patients on apixaban and rivaroxaban. Drug Des. Devel. Ther.  17, 2513\u20132522. https:\/\/doi.org\/10.2147\/DDDT.S417096  (2023).","DOI":"10.2147\/DDDT.S417096"},{"key":"90405_CR60","doi-asserted-by":"publisher","unstructured":"Attelind, S. et al. Genetic determinants of apixaban plasma levels and their relationship to bleeding and thromboembolic events. Front. Genet. 13, 89. https:\/\/doi.org\/10.3389\/fgene.2022.982955 (2022).","DOI":"10.3389\/fgene.2022.982955"},{"issue":"3","key":"90405_CR61","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1111\/j.1742-7843.2005.pto_973160.x","volume":"97","author":"MS Faber","year":"2005","unstructured":"Faber, M. S., Jetter, A. & Fuhr, U. Assessment of CYP1A2 activity in clinical practice: why, how, and when? Basic. Clin. Pharmacol. Toxicol. 97(3), 125\u2013134. https:\/\/doi.org\/10.1111\/j.1742-7843.2005.pto_973160.x (2005).","journal-title":"Basic. Clin. Pharmacol. Toxicol."},{"key":"90405_CR62","doi-asserted-by":"publisher","unstructured":"Krekels, E. H. J., Rower, J. E., Constance, J. E., Knibbe, C. A. J. & Sherwin, C. M. T. Chapter 8\u2014hepatic drug metabolism in Pediatric patients. In Drug Metabolism in Diseases (ed. Xie, W.)  181\u2013206 (Academic, 2017). https:\/\/doi.org\/10.1016\/B978-0-12-802949-7.00008-0.","DOI":"10.1016\/B978-0-12-802949-7.00008-0"},{"key":"90405_CR63","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1007\/978-1-4615-0135-0_47","volume":"527","author":"RK Sindhu","year":"2003","unstructured":"Sindhu, R. K. & Vaziri, N. D. Upregulation of cytochrome P450 1A2 in chronic renal failure: does oxidized tryptophan play a role? Adv. Exp. Med. Biol. 527, 401\u2013407. https:\/\/doi.org\/10.1007\/978-1-4615-0135-0_47 (2003).","journal-title":"Adv. Exp. Med. Biol."},{"key":"90405_CR64","doi-asserted-by":"publisher","unstructured":"Xiong, L. et al. Direct androgen receptor regulation of sexually dimorphic gene expression in the mammalian kidney. BioRxiv Prepr. Serv. Biol. 2023, 539585. https:\/\/doi.org\/10.1101\/2023.05.06.539585  (2023).","DOI":"10.1101\/2023.05.06.539585"},{"key":"90405_CR65","doi-asserted-by":"publisher","unstructured":"Breljak, D., Brzica, H., Sweet, D. H., Anzai, N. & Sabolic, I. Sex-dependent expression of Oat3 (Slc22a8) and Oat1 (Slc22a6) proteins in murine kidneys. Am J. Physiol. Ren. Physiol. 304(8), F1114\u2013F1126. https:\/\/doi.org\/10.1152\/ajprenal.00201.2012 (2013).","DOI":"10.1152\/ajprenal.00201.2012"},{"key":"90405_CR66","doi-asserted-by":"publisher","unstructured":"Sakurai, Y. et al. Expression levels of renal organic anion transporters (OATs) and their correlation with anionic drug excretion in patients with renal diseases. Pharm. Res. 21(1), 61\u201367. https:\/\/doi.org\/10.1023\/B:PHAM.0000012153.71993.cb (2004).","DOI":"10.1023\/B:PHAM.0000012153.71993.cb"},{"key":"90405_CR67","doi-asserted-by":"publisher","unstructured":"Zhang, J., Wang, H., Fan, Y., Yu, Z. & You, G. Regulation of organic anion transporters: role in physiology, pathophysiology, and drug elimination. Pharmacol. Ther. 217, 107647. https:\/\/doi.org\/10.1016\/j.pharmthera.2020.107647 (2021).","DOI":"10.1016\/j.pharmthera.2020.107647"},{"key":"90405_CR68","doi-asserted-by":"publisher","unstructured":"Deguchi, T. et al. Characterization of uremic toxin transport by organic anion transporters in the kidney. Kidney Int. 65(1), 162\u2013174. https:\/\/doi.org\/10.1111\/j.1523-1755.2004.00354.x (2004).","DOI":"10.1111\/j.1523-1755.2004.00354.x"},{"key":"90405_CR69","doi-asserted-by":"publisher","unstructured":"Ravid, J. D. & Chitalia, V. C. Molecular mechanisms underlying the cardiovascular toxicity of specific uremic solutes.  Cells  9(9),  2020. https:\/\/doi.org\/10.3390\/cells9092024   (2024)","DOI":"10.3390\/cells9092024"},{"issue":"14","key":"90405_CR70","doi-asserted-by":"publisher","first-page":"1862","DOI":"10.2174\/1381612821666150302115025","volume":"21","author":"P Lee","year":"2015","unstructured":"Lee, P. & Wu, X. Modifications of human serum albumin and their binding effect. Curr. Pharm. Des. 21(14), 1862\u20131865 (2015).","journal-title":"Curr. Pharm. Des."},{"key":"90405_CR71","doi-asserted-by":"publisher","unstructured":"Yu, S. et al. Interaction of human serum albumin with uremic toxins: a thermodynamic study. RSC Adv. 7, 27913\u201327922. https:\/\/doi.org\/10.1039\/C7RA02838E (2017).","DOI":"10.1039\/C7RA02838E"},{"key":"90405_CR72","doi-asserted-by":"publisher","unstructured":"Wang, Q. et al. Determination of potential main sites of apixaban binding in human serum albumin by combined spectroscopic and docking investigations. RSC Adv.  5(99),  81696\u201381706. https:\/\/doi.org\/10.1039\/C5RA15430H   (2015).","DOI":"10.1039\/C5RA15430H"},{"key":"90405_CR73","doi-asserted-by":"publisher","unstructured":"Devine, E., Krieter, D. H., R\u00fcth, M., Jankovski, J. & Lemke, H. D. Binding affinity and capacity for the uremic toxin indoxyl sulfate.  Toxins  6(2), 416\u2013429. https:\/\/doi.org\/10.3390\/toxins6020416 (2014).","DOI":"10.3390\/toxins6020416"},{"key":"90405_CR74","doi-asserted-by":"publisher","unstructured":"Sakai, T. et al. Interaction mechanism between indoxyl sulfate, a typical uremic toxin bound to site II, and ligands bound to site I of human serum albumin. Pharm. Res.  18(4), 520\u2013524.  https:\/\/doi.org\/10.1023\/A:1011014629551   (2001).","DOI":"10.1023\/A:1011014629551"},{"key":"90405_CR75","doi-asserted-by":"publisher","unstructured":"Su, L. et al. Abcb1a and Abcb1b genes function differentially in blood\u2013testis barrier dynamics in the rat. Cell. Death Dis. 8(9), 9. https:\/\/doi.org\/10.1038\/cddis.2017.435 (2017).","DOI":"10.1038\/cddis.2017.435"},{"key":"90405_CR76","doi-asserted-by":"publisher","unstructured":"Horsey, A. J., Cox, M. H., Sarwat, S. & Kerr, I. D. The multidrug transporter ABCG2: still more questions than answers.  Biochem. Soc. Trans. 44(3),  824\u2013830. https:\/\/doi.org\/10.1042\/BST20160014   (2016).","DOI":"10.1042\/BST20160014"},{"key":"90405_CR77","doi-asserted-by":"publisher","unstructured":"Grishanova, A. Y. & Perepechaeva, M. L. Aryl hydrocarbon receptor in oxidative stress as a double agent and its biological and therapeutic significance. Int. J. Mol. Sci.  23(12), 12. https:\/\/doi.org\/10.3390\/ijms23126719  (2022).","DOI":"10.3390\/ijms23126719"},{"key":"90405_CR78","doi-asserted-by":"publisher","unstructured":"Wang, L. et al. In vitro assessment of metabolic drug-drug interaction potential of apixaban through cytochrome P450 phenotyping, inhibition, and induction studies. Drug Metab. Dispos. Biol. Fate Chem. 38(3),  448\u2013458. https:\/\/doi.org\/10.1124\/dmd.109.029694   (2010).","DOI":"10.1124\/dmd.109.029694"},{"key":"90405_CR79","doi-asserted-by":"publisher","unstructured":"Lu, C. L. et al. Indoxyl-sulfate-induced redox imbalance in chronic kidney disease. Antioxidants  10(6), 936. https:\/\/doi.org\/10.3390\/antiox10060936  (2021).","DOI":"10.3390\/antiox10060936"},{"key":"90405_CR80","doi-asserted-by":"publisher","unstructured":"Sekine, T., Miyazaki, H. & Endou, H. Molecular physiology of renal organic anion transporters. Am. J. Physiol. -Ren. Physiol. 290(2), F251\u2013F261. https:\/\/doi.org\/10.1152\/ajprenal.00439.2004 (2006).","DOI":"10.1152\/ajprenal.00439.2004"},{"key":"90405_CR81","doi-asserted-by":"publisher","unstructured":"Perez-Riverol, Y. et al. The PRIDE database resources in 2022: a hub for mass spectrometry-based proteomics evidences. Nucleic Acids Res. 50, D543\u2013D552. https:\/\/doi.org\/10.1093\/nar\/gkab1038 (2022).","DOI":"10.1093\/nar\/gkab1038"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-90405-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-90405-5","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-90405-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,19]],"date-time":"2025-02-19T10:32:39Z","timestamp":1739961159000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-90405-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,19]]},"references-count":81,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["90405"],"URL":"https:\/\/doi.org\/10.1038\/s41598-025-90405-5","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-4945804\/v1","asserted-by":"object"}]},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,19]]},"assertion":[{"value":"20 August 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 February 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 February 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"6075"}}