中國醫藥大學機構典藏 China Medical University Repository, Taiwan:Item 310903500/58291
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    Please use this identifier to cite or link to this item: http://ir.cmu.edu.tw/ir/handle/310903500/58291


    Title: Warfarin 與乳腺癌耐藥蛋白之相關性及其與蔓越莓交互作用機制之探討
    Studies on the association of warfarin with BCRP and the underlying mechanisms of warfarin － cranberry interaction
    Authors: 楊孟璇;Meng-Syuan Yang
    Contributors: 藥學系博士班
    Keywords: warfarin;蔓越莓 － warfarin 交互作用;藥物動力學;藥效學;國際標準化凝血?原時間比;乳腺癌耐藥蛋白;細胞色素 P 450;cranberry － warfarin interaction;pharmacokinetics;pharmacodynamics;International Normalized Ratio;breast cancer resistance protein;cytochrome P 450
    Date: 2017-07-25
    Issue Date: 2018-01-15 09:30:51 (UTC+8)
    Publisher: 中國醫藥大學
    Abstract: Warfarin 為?床上重要且應用廣泛的口服抗凝血藥物，治療指數狹窄。迄今臨床上仍有許多藥物、中藥、食物、保健食品與 warfarin 之間的交互作用陸續發生，且機轉尚未完全明朗。Warfarin 的 pKa 為 4.94，於腸腔及血循環中主要以陰離子存在，我們推測其體內運送須藉由陰離子轉運蛋白之媒介。乳腺癌耐藥蛋白 (breast cancer resistance protein，BCRP) 為一外排型轉運蛋白，其受質包含許多陰離子。因此，本研究首先證明 warfarin 為 BCRP 之受質。另外，亦探討蔓越莓與 warfarin 之交互作用及相關機轉。
    我們利用 BCRP 過度表達細胞及 BCRP 基因剔除小鼠，以 LC-MS 定量細胞及血漿中 R-warfarin、S-warfarin 之含量，證明它們是否為 BCRP 之受質。另以大鼠探討不同時間併服蔓越莓後，對 warfarin 藥動學及抗凝血活性之影響，並探索相關機轉。
    細胞及動物的結果皆顯示，R-warfarin、S-warfarin 為 BCRP 之受質。此外，不同時間併服蔓越莓後，對 R-warfarin、S-warfarin 之藥動學/藥效學造成的影響不同，先服蔓越莓造成 R-warfarin、S-warfarin 之全身暴露降低；而後服蔓越莓造成 S-warfarin 之 AUC48-96 及國際標準化凝血酶原時間比 (International Normalized Ratio，INR) 顯著增高，其機轉與 BCRP 相關。我們建議服用 warfarin 的病人，應避免服用蔓越莓，以維持穩定的療效。
    本研究為首次證實 R-warfarin、S-warfarin 為 BCRP 之受質，並釐清蔓越莓與 warfarin 臨床上呈現雙向交互作用的原因是由於蔓越莓併服時間的不同所導致。此新發現對 warfarin 之藥動學及臨床交互作用提供了重要的基礎資訊，未來可應用於預測並避免交互作用之發生，期能有助於病人用藥安全之提升。
    Warfarin, a racemate of R- and S-warfarin, is an important oral anticoagulant with narrow therapeutic window. Till now, numerous unexpected interactions of drugs, herbs, foods, dietary supplements with warfarin were still emerging in clinical practice, and the interactions remained not fully explainable by known mechanisms. Warfarin is an acidic drug (pKa 4.94) and mainly exists as anionic form in gut lumen and bloodstream. We hypothesized that the transport of warfarin anion across cell membrane was mediated by breast cancer resistance protein (BCRP), an efflux transporter having a variety of anion substrates. This study aimed to verify whether R- and S-warfarin are substrates of BCRP. In addition, the underlying mechanisms of cranberry – warfarin interaction were explored.

    BCRP-overexpressing cells and BCRP-/- mice were used for transport and pharmacokinetic/pharmacodynamic studies, respectively. The concentrations of R- and S-warfarin in cell and plasma specimens were simultaneously determined by LC-MS method. In addition, the effects of cranberry given at different time on warfarin pharmacokinetics and INR were evaluated in rats, and the proposed mechanisms were verified by using in vitro models.

    Cell and animal studies consistently showed that R- and S-warfarin were transported by BCRP. Coadministration with cranberry at 0.5 h before warfarin dosing significantly decreased the systemic exposure of R- and S-warfarin via activation of intestine BCRP. However, coadministration with cranberry at 10 h after warfarin dosing significantly increased the AUC48-96 and INR through inhibition of BCRP by cranberry metabolites. We thus suggest that patients treated with warfarin should avoid ingestion of cranberry to prevent pharmacokinetic interaction.

    This is the first study to disclose that R- and S-warfarin were transported by BCRP, and clarify that the reason of the bidirectional interaction between cranberry and warfarin was due to different coadministration time of cranberry. This discovery would provide valuable information for better understanding the pharmacokinetics and clinical interactions of warfarin, which would help to predict and avoid warfarin interactions in the future, hopefully, the safety of warfarin utilization could be improved.
    Appears in Collections:[School of Pharmacy/Master Degree Program, Ph. D program] Theses & dissertations

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