Changes in Pharmacodynamic Parameters during Co-administration of 5-FU with Warfarin: A Retrospective Case Series

Tayag, Jose Carlos S.; Ishii, Takeo; Kokuba, Shun; Hirata, Tetsuya; Shiohira, Hideo; Nakamura, Katsunori

doi:10.1248/bpb.b22-00129

Cited by 1 publication

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“…As a newly approved anti-tumor adjuvant drug, it is inevitable that ICT will be combined with other drugs in clinical application. For example, anticoagulation therapy is common among cancer patients due to the high risk of cancer-associated thromboembolic events (Tayag et al, 2022). Therefore, warfarin, as one of the most clinically used anticoagulants, is likely to be prescribed along with ICT.…”

Section: Discussionmentioning

confidence: 99%

Mechanistic Study of Icaritin-Induced Inactivation of Cytochrome P450 2C9

et al. 2023

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Icaritin (ICT) is a prenylflavonoid derivative that has been approved by NMPA for the treatment of hepatocellular carcinoma. This study aims to evaluate the potential inhibitory effect of ICT against cytochrome P450 enzymes and to elucidate the inactivation mechanisms. Results showed that ICT inactivated CYP2C9 in a time, concentration, and NADPH-dependent manner with K i = 1.896 μM, K inact = 0.02298 minutes -1 , and K inact /Ki = 12 minutes -1 mM -1 , whereas the activities of rest CYP isozymes was minimally affected. Additionally, the presence of CYP2C9 competitive inhibitor, sulfaphenazole, SOD/CAT system, and GSH all protected CYP2C9 from ICT-induced activity loss. Moreover, the activity loss was neither recovered by washing the ICT-CYP2C9 preincubation mixture nor the addition of potassium ferricyanide. These results, collectively, implied the underlying inactivation mechanism involved the covalent binding of ICT to the apoprotein and/or the prosthetic heme of CYP2C9. Furthermore, an ICT-quinone methide (QM)-derived GSH adduct was identified and human glutathione S-transferases (GST) isozymes GSTA1-1, GSTM1-1, and GSTP1-1 were shown to substantially involved in the detoxification of ICT-QM. Interestingly, our systematic molecular modeling work predicted that ICT-QM was covalently bind to C216, a cysteine residue located in the F-G loop downstream of substrate recognition site 2 (SRS2) in CYP2C9. The sequential molecular dynamics simulation confirmed the binding to C216 induced a conformational change in the active catalytic center of CYP2C9. Lastly, the potential risks of clinical drug-drug interactions triggered by ICT as a perpetrator were This article has not been copyedited and formatted. The final version may differ from this version.

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Section: Discussionmentioning

confidence: 99%