JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
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2019
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IF 2.983
Ting Tai,Huan Zhou,Ting Zhu,Yu-Meng Jia,Jin-Zi Ji,Yi-Fei Li,Qiong-Yu Mi,Hong-Guang Xie
Vicagrel is a promising novel antiplatelet drug. However, the quantification of vicagrel in plasma is currently unavailable since it is liable to be hydrolyzed in plasma by esterases. In this study, an optimized strategy was developed and validated to stabilize vicagrel, 2-oxo-clopidogrel (thiolactone metabolite), and H4 (active thiol metabolite) before quantification of the analytes, such as addition of citric acid (for plasma acidification) and NaF (a non-specific esterase inhibitor) to inhibit esterase activity, immediate addition of a thiol-alkylating reagent MPB into blood samples to derivatize H4 for the formation of stable H4 derivative (i.e., MP-H4), use of the anticoagulant K 2 EDTA to minimize the conversion of 2-oxo-clopidogrel to H-endo, and keeping the analytes at 4 °C or on wet ice to minimize degradation of the analytes when processed and analyzed. The stability was measured as percent of each analyte remained in plasma samples after their storage for 4 h at 4 °C or in blood samples after 1 h at 4 °C. The results indicated that stability of vicagrel was increased significantly in stabilized plasma or blood samples compared with non-stabilized controls for rats and humans, respectively, and that the stability of 2-oxo-clopidogrel was increased to a certain extent. In contrast, MP-H4 formed was stable in plasma immediately after thorough mixture of MPB with blood. We conclude that the above strategy is useful for improving the stability of vicagrel, 2-oxo-clopidogrel, and H4 in rat or human plasma, and that vicagrel and its two major metabolites can be quantified accurately and simultaneously.
研究领域:
药理学
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分析化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOPHARMACEUTICS & DRUG DISPOSITION
·
2022
·Vol. 43
·期 6
·247-254
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IF 1.831
Ting Zhu,Yu Wu,Xue-Mei Li,Yu-Meng Jia,Huan Zhou,Li-Ping Jiang,Ting Tai,Qiong-Yu Mi,Jin-Zi Ji,Hong-Guang Xie
As an analog of clopidogrel and prasugrel, vicagrel is completely hydrolyzed to intermediate thiolactone metabolite 2-oxo-clopidogrel (also the precursor of active thiol metabolite H4) in human intestine, predominantly by AADAC and CES2; however, other unknown vicagrel hydrolases remain to be identified. In this study, recombinant human Raf kinase inhibitor protein (rhRKIP) and pooled human intestinal S9 (HIS9) fractions and microsome (HIM) preparations were used as the different enzyme sources; prasugrel as a probe drug for RKIP (a positive control), vicagrel as a substrate drug of interest, and the rate of the formation of thiolactone metabolites 2-oxo-clopidogrel and R95913 as metrics of hydrolase activity examined, respectively. In addition, an IC 50 value of inhibition of rhRKIP-catalyzed vicagrel hydrolysis by locostatin was measured, and five classical esterase inhibitors with distinct esterase selectivity were used to dissect the involvement of multiple hydrolases in vicagrel hydrolysis. The results showed that rhRKIP hydrolyzed vicagrel in vitro, with the values of K m , V max , and CL int measured as 20.04 ± 1.99 μM, 434.60 ± 12.46 nM/min/mg protein, and 21.69 ± 0.28 ml/min/mg protein, respectively, and that an IC 50 value of locostatin was estimated as 1.24 ± 0.04 mM for rhRKIP. In addition to locostatin, eserine and vinblastine strongly suppressed vicagrel hydrolysis in HIM. It is concluded that RKIP can catalyze the hydrolysis of vicagrel in the human intestine, and that vicagrel can be hydrolyzed by multiple hydrolases, such as RKIP, AADAC, and CES2, concomitantly.
研究领域:
药理学
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生物化学
✓ 已验证
DOI
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
·
2021
·
IF 5.194
Shuaibing Liu,Ziteng Wang,Eric Chan,Yibo Zhao,Jian Kang,Xiaojian Zhang,Xin Tian
Vicagrel, an antiplatelet drug candidate targeting platelet P2Y 12 receptor and has finished its phase II clinical trial . The inhibition of six major cytochrome P450 enzymes (P450) (CYP2B6, CYP2C8 , CYP2C9 , CYP2C19 , CYP2D6 , and CYP3A4) and six UDP-glucuronosyltransferases (UGT) (UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, and UGT2B7) by vicagrel was evaluated using pooled human liver microsomes and specific probe substrates. Physiology-based pharmacokinetic (PBPK) simulation was further applied to predict the in vivo drug-drug interaction (DDI) potential between vicagrel and bupropion as well as S-mephenytoin. The results suggested that vicagrel inhibited CYP2B6 and CYP2C19 potently with apparent IC 50 values of 1.6 and 2.0 μM, respectively. In terms of mode of reversible inhibition, vicagrel exhibited mixed-type inhibition of CYP2B6-catalyzed bupropion hydroxylation and noncompetitive inhibition of CYP2C19-mediated S-mephenytoin 4′-hydroxylation with K i values of 0.19 μM and 1.2 μM, respectively. Vicagrel displayed profound time-dependent inhibition towards CYP2B6 with maximal rate constant of inactivation ( k inact ) and half-maximal inactivator concentration ( K I ) values of 0.062 min −1 and 1.52 μM, respectively. No time-dependent inhibition by vicagrel was noted for CYP2C19. For UGT, negligible to moderate inhibition by vicagrel was observed with IC 50 values of >50.0, >50.0, 28.2, 8.7, >50.0 and 28.2 μM for UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9 and UGT2B7, respectively. In terms of mode of reversible inhibition, vicagrel exhibited mixed-type inhibition of UGT1A6-catalyzed N-Acetylserotonin β-D-glucuronidation with a K i value of 5.6 μM. No time-dependent inhibition by vicagrel was noted for UGT1A6. PBPK simulation indicated that neither altered AUC nor C max of bupropion and S-mephenytoin was observed in the presence of vicagrel. Our study provides inhibitory constants for future DDI prediction between vicagrel and drug substrates of CYP2B6, CYP2C19 and UGT1A6. In addition, our simulation suggests the lack of clinically important DDI between vicagrel and bupropion or S-mephenytoin.
研究领域:
药理学
·
制药学
·
临床试验
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）