Evaluation and clinical implications of interactions between compound Danshen dropping pill and warfarin associated with the epoxide hydrolase gene
Introduction: In clinical practice, warfarin is often combined with Compound Danshen dripping pill (CDDP) for the treatment of cardiovascular diseases. However, warfarin has a narrow therapeutic index, wide interindividual variability (genetic and non-genetic factors), and is susceptible to drug-dru...
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| Format: | Article |
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Frontiers Media S.A.
2023-05-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2023.1105702/full |
| _version_ | 1797833578364534784 |
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| author | Xixi Chen Xixi Chen Xurui Zuo Yingqiang Zhao Yuhong Huang Chunxiao Lv |
| author_facet | Xixi Chen Xixi Chen Xurui Zuo Yingqiang Zhao Yuhong Huang Chunxiao Lv |
| author_sort | Xixi Chen |
| collection | DOAJ |
| description | Introduction: In clinical practice, warfarin is often combined with Compound Danshen dripping pill (CDDP) for the treatment of cardiovascular diseases. However, warfarin has a narrow therapeutic index, wide interindividual variability (genetic and non-genetic factors), and is susceptible to drug-drug interactions. Our previous study indicated that CDDP might interact with warfarin in individuals with the epoxide hydrolase gene (EPHX1; single-nucleotide polymorphism: rs2292566) A/A subtype. We sought to clarify the interaction between CDDP and warfarin associated with EPHX1 in a comprehensive and accurate manner.Methods: Here, EPHX1 A and EPHX1 G cell lines were established. Expression of microsomal epoxide hydrolase (mEH), vitamin K epoxide reductase (VKOR), and vitamin K-dependent clotting factors (FII, FVII, FIX, FX) was measured by western blotting upon incubation with CDDP and warfarin. mEH activity was evaluated by measuring the transformation of epoxyeicosatrienoic acids into dihydroxyeicosatrienoic acids. Then, healthy volunteers (HVs) with the EPHX1 A/A genotype were recruited and administered warfarin and CDDP to investigate the pharmacokinetics and pharmacodynamics of warfarin.Results: CDDP combined with warfarin could decrease expression of mEH and VKOR, and increase protein expression of FII, FVII, FIX, and FX, in EPHX1 A cells. CDDP could slightly influence the pharmacokinetics/pharmacodynamics of warfarin in HVs with the EPHX1 A/A genotype.Discussion: Rational combination of CDDP and warfarin was safe with no risk of bleeding, but the therapeutic management is also needed. The clinical study is posted in the China Clinical Trial Registry (ChiCTR190002434). |
| first_indexed | 2024-04-09T14:26:16Z |
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| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-09T14:26:16Z |
| publishDate | 2023-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-9a722d3f544c45b4bd498b3be0adff8b2023-05-04T04:31:27ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122023-05-011410.3389/fphar.2023.11057021105702Evaluation and clinical implications of interactions between compound Danshen dropping pill and warfarin associated with the epoxide hydrolase geneXixi Chen0Xixi Chen1Xurui Zuo2Yingqiang Zhao3Yuhong Huang4Chunxiao Lv5Department of Clinical Pharmacology, Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, ChinaDepartment of Cardiology, Qingdao Hiser Hospital Affiliated of Qingdao University (Qingdao Traditional Chinese Medicine Hospital), Qingdao, ChinaDepartment of Clinical Pharmacology, Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, ChinaDepartment of Cardiology, Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, ChinaDepartment of Clinical Pharmacology, Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, ChinaDepartment of Clinical Pharmacology, Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, ChinaIntroduction: In clinical practice, warfarin is often combined with Compound Danshen dripping pill (CDDP) for the treatment of cardiovascular diseases. However, warfarin has a narrow therapeutic index, wide interindividual variability (genetic and non-genetic factors), and is susceptible to drug-drug interactions. Our previous study indicated that CDDP might interact with warfarin in individuals with the epoxide hydrolase gene (EPHX1; single-nucleotide polymorphism: rs2292566) A/A subtype. We sought to clarify the interaction between CDDP and warfarin associated with EPHX1 in a comprehensive and accurate manner.Methods: Here, EPHX1 A and EPHX1 G cell lines were established. Expression of microsomal epoxide hydrolase (mEH), vitamin K epoxide reductase (VKOR), and vitamin K-dependent clotting factors (FII, FVII, FIX, FX) was measured by western blotting upon incubation with CDDP and warfarin. mEH activity was evaluated by measuring the transformation of epoxyeicosatrienoic acids into dihydroxyeicosatrienoic acids. Then, healthy volunteers (HVs) with the EPHX1 A/A genotype were recruited and administered warfarin and CDDP to investigate the pharmacokinetics and pharmacodynamics of warfarin.Results: CDDP combined with warfarin could decrease expression of mEH and VKOR, and increase protein expression of FII, FVII, FIX, and FX, in EPHX1 A cells. CDDP could slightly influence the pharmacokinetics/pharmacodynamics of warfarin in HVs with the EPHX1 A/A genotype.Discussion: Rational combination of CDDP and warfarin was safe with no risk of bleeding, but the therapeutic management is also needed. The clinical study is posted in the China Clinical Trial Registry (ChiCTR190002434).https://www.frontiersin.org/articles/10.3389/fphar.2023.1105702/fullwarfarincompound Danshen dripping pillepoxide hydrolase gene (EPHX1)microsomal epoxide hydrolase (mEH)pharmacokineticpharmacodynamics |
| spellingShingle | Xixi Chen Xixi Chen Xurui Zuo Yingqiang Zhao Yuhong Huang Chunxiao Lv Evaluation and clinical implications of interactions between compound Danshen dropping pill and warfarin associated with the epoxide hydrolase gene Frontiers in Pharmacology warfarin compound Danshen dripping pill epoxide hydrolase gene (EPHX1) microsomal epoxide hydrolase (mEH) pharmacokinetic pharmacodynamics |
| title | Evaluation and clinical implications of interactions between compound Danshen dropping pill and warfarin associated with the epoxide hydrolase gene |
| title_full | Evaluation and clinical implications of interactions between compound Danshen dropping pill and warfarin associated with the epoxide hydrolase gene |
| title_fullStr | Evaluation and clinical implications of interactions between compound Danshen dropping pill and warfarin associated with the epoxide hydrolase gene |
| title_full_unstemmed | Evaluation and clinical implications of interactions between compound Danshen dropping pill and warfarin associated with the epoxide hydrolase gene |
| title_short | Evaluation and clinical implications of interactions between compound Danshen dropping pill and warfarin associated with the epoxide hydrolase gene |
| title_sort | evaluation and clinical implications of interactions between compound danshen dropping pill and warfarin associated with the epoxide hydrolase gene |
| topic | warfarin compound Danshen dripping pill epoxide hydrolase gene (EPHX1) microsomal epoxide hydrolase (mEH) pharmacokinetic pharmacodynamics |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2023.1105702/full |
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