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Int J Surg
Int J Surg
JS9
International Journal of Surgery (London, England)
1743-9191
1743-9159
Lippincott Williams & Wilkins Hagerstown, MD

38814293
IJS-D-24-02026
10.1097/JS9.0000000000001732
00115
3
Correspondence
Comment on ‘Exploring the complex relationship between vitamin K, gut microbiota, and warfarin variability in cardiac surgery patients’
Zhou Zhiling MS a1399463519@qq.com

Jiang Chaoying MS bjiangcy@enzemed.com

Ren Yu MM reny4147@enzemed.com
c*
a Department of Medicine, Wenzhou Medical University, Wenzhou
b Department of Orthopedic, Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University
c Department of Pharmacy, Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Taizhou, Zhejiang, People’s Republic of China
* Corresponding author. Address: Department of Pharmacy, Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, No. 150 Ximen Road, Taizhou 317000, Zhejiang, People’s Republic of China. Tel.: +86 130 7364 7921. E-mail: reny4147@enzemed.com (Y. Ren).
9 2024
29 5 2024
110 9 59735974
14 5 2024
19 5 2024
Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/

OPEN-ACCESSTRUE
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pmc Dear Editor,

We read with great interest the article by Xue et al.1 titled ‘Exploring the complex relationship between vitamin K, gut microbiota, and warfarin variability in cardiac surgery patients.’ Xue et al. began by discussing how fluctuations in vitamin K levels can influence the anticoagulant effect of warfarin. They delved into the potential connection between gut microbiota and warfarin variability. Utilizing a PK-PD model, they predicted the INR in 256 cardiac surgery patients following warfarin administration. By measuring serum warfarin and vitamin K levels, as well as extracting bacterial genomic DNA from fecal samples to identify bacterial species and their abundance, they sought to investigate the impact of vitamin K levels and gut microbiota on individual differences in warfarin response. It is commendable that this study is the first to propose a connection between vitamin K levels, gut microbiota, and warfarin variability, offering novel and valuable insights into the exploration of individual differences in warfarin response. The research focuses on evaluating the relationships between vitamin K levels, gut microbiota, and the pharmacokinetic and pharmacodynamic parameters of warfarin, thus addressing a relatively underexplored area in the study of warfarin variability. While we acknowledge the authors’ research efforts, several aspects warrant further discussion.

Firstly, the study overlooks the impact of genetic variations in warfarin metabolism on vitamin K levels and gut microbiota. Extensive research has shown that polymorphisms in the genes encoding cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) can lead to reduced warfarin requirements and may be associated with an increased risk of adverse clinical reactions2. The demographic data section of the study lists the number of patients with each CYP2C9 and VKORC1 genotype but does not provide detailed information on these genotypes. Pharmacogenomic studies have demonstrated that genetic polymorphisms in VKORC1 and CYP2C9 contribute to 6–37% and 5–22% of the variability in warfarin dosage requirements, respectively3. These genes significantly influence warfarin metabolism and play a critical role in individual dosage variability. The warfarin dose required to achieve the same anticoagulant effect can vary up to 20-fold between individuals with different genotypes4. In this study, all patients underwent warfarin genotyping. A more detailed exploration of how genetic differences in warfarin metabolism affect vitamin K levels and gut microbiota would further strengthen the research.

Secondly, the approach of modeling voriconazole-treated patients as if they were treated with fluconazole needs refinement. In this study, 13 patients were treated with voriconazole, but it was not included as a covariate in the previously established PK-PD model. Instead, fluconazole was used as a covariate to reduce prediction bias, treating voriconazole as if it were fluconazole. However, the CYP enzyme inhibition profiles of voriconazole and fluconazole are not identical, making this substitution inaccurate. Fluconazole is a strong inhibitor of CYP2C9 and a moderate inhibitor of CYP3A4, significantly inhibiting the metabolism of both S- and R-warfarin. Black et al.5 demonstrated that taking fluconazole (400 mg/day) for 6 days significantly reduced the metabolism of S-warfarin via CYP2C9, inhibiting approximately 70% of warfarin metabolism and significantly increasing the intensity and duration of anticoagulation. Voriconazole, however, is primarily metabolized by CYP2C19, with secondary metabolism by CYP2C9 and CYP3A4. Therefore, the appropriateness of substituting one model for the other remains questionable, and the differences in prediction model errors have yet to be definitively resolved.

This study explores the relationship between vitamin K levels, gut microbiota, and warfarin variability, offering novel and valuable insights into the individual differences in warfarin response. Addressing the aforementioned suggestions would significantly enhance the study’s rigor, clinical applicability, and relevance.

Ethical approval

Not applicable.

Consent

Not applicable.

Sources of funding

This study was supported by Enze Medical Center (Group) Scientific Research (No. 24EZB07).

Author contribution

Y.R.: proposed the design, collected, and wrote the study; Z.Z. and C.J.: structured the content.

Conflicts of interest disclosure

There are no conflicts of interest.

Research registration unique identifying number (UIN)

Not applicable.

Guarantor

Yu Ren.

Data availability statement

This letter does not involve any data.

Provenance and peer review

Commentary, internally reviewed.

Acknowledgements

Not applicable.

Zhiling Zhou and Chaoying Jiang have contributed equally to this work and share first authorship.

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Published online 29 May 2024
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References

1 Xue L Singla RK Qin Q . Exploring the complex relationship between vitamin K, gut microbiota, and warfarin variability in cardiac surgery patients. Int J Surg 2023;109 :3861–3871.37598356
2 Rieder MJ Reiner AP Gage BF . Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Engl J Med 2005;352 :2285–2293.15930419
3 Aithal GP Day CP Kesteven PJ . Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet 1999;353 :717–719.10073515
4 Higashi MK Veenstra DL Kondo LM . Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. JAMA 2002;287 :1690–1698.11926893
5 Black DJ Kunze KL Wienkers LC . Warfarin-fluconazole. II. A metabolically based drug interaction: in vivo studies. Drug Metab Dispos 1996;24 :422–428.8801057
