PHARMAZIE
·
2012
·Vol. 67
·期 8
·715-717
·
IF 1.006
Fu Jian-Fang,Ren Qin-You,Zhang Nan-Yan,Gao Bin,Tu Yan-Yang,Fu Guo-Qiang,Li Dao-Hai,Zhang Yong-Sheng
The aim of the present study was to investigate the inhibitory potential of glimepiride towards important UDP-glucuronosyltransferase (UGT) isoforms in human liver, which play a key role in the elimination of drugs. The recombinant UGT enzymes were used as enzyme source, and a nonspecific
substrate 4-methylumbelliferone (4-MU) was utilized as substrate. The results showed that 100 μM of glimepiride inhibited UGT1A1, UGT1A3, UGT1A6, UGT1A9, UGT2B7 and UGT2B15 by 54.7%, 43.1%, 100%, 70.5%, 32.7 and 37.2%, respectively. Given that glimepiride exhibited strong inhibition towards
UGT1A6, further inhibitory kinetic behaviour was determined. Glimepiride exerted concentration-dependent inhibition towards UGT1A6. Both Dixon and Lineweaver-Burk plots demonstrated that inhibition of UGT1A6 was best fit for noncompetitive inhibition type, and the inhibition kinetic parameter
(Ki) was calculated to be 59.8 μM. Given that UGT1A6 plays a key role in detoxification of many drugs, more attention should be given when glimepiride was co-administered with the drugs mainly undergoing UGT1A6-mediated metabolism.
研究领域:
药理学
·
临床医学
✓ 已验证
产品关联
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
MOLECULES
·
2023
·Vol. 28
·期 3
·1479
·
IF 4.6
Shuai Liu,Keming Zheng,Yilin Jiang,Susu Gai,Bohan Li,Dehai Li,Shuang Yang,Zhihua Lv
Penindolone (PND) is a novel broad-spectrum anti-Influenza A Virus (IAV) agent blocking hemagglutinin-mediated adsorption and membrane fusion. The goal of this work was to reveal the metabolic route of PND in rats. Ultra-high-performance liquid chromatography tandem high-resolution mass spectrometry (UHPLC–HRMS) was used for metabolite identification in rat bile, feces and urine after administration of PND. A total of 25 metabolites, including 9 phase I metabolites and 16 phase II metabolites, were characterized. The metabolic pathways were proposed, and metabolites were visualized via Global Natural Product Social Molecular Networking (GNPS). It was found that 65.24–80.44% of the PND presented in the formation of glucuronide conjugate products in bile, and more than 51% of prototype was excreted through feces. In in vitro metabolism of PND by rat, mouse and human liver microsomes (LMs) system, PND was discovered to be eliminated in LMs to different extents with significant species differences. The effects of chemical inhibitors of isozymes on the metabolism of PND in vitro indicated that CYP2E1/2C9/3A4 and UGT1A1/1A6/1A9 were the metabolic enzymes responsible for PND metabolism. PND metabolism in vivo could be blocked by UGTs inhibitor (ibrutinib) to a certain extent. These findings provided a basis for further research and development of PND.Keywords:penindolone;biotransformation;metabolite;liquid chromatography–mass spectrometry
研究领域:
药理学
·
病毒学
·
分析化学
·
药物代谢
✓ 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）