瑞格非尼对人尿苷二磷酸葡糖醛酸转移酶活性抑制作用的体外研究

发布时间：2018-03-11 02:09

本文选题：瑞格非尼　切入点：尿苷二磷酸葡糖醛酸转移酶　出处：《药学学报》2017年11期 　论文类型：期刊论文

【摘要】：应用体外人肝微粒体及重组人源代谢酶孵育体系考察了瑞格非尼(regorafenib,REG)对12种人尿苷二磷酸葡糖醛酸转移酶(UGTs)的抑制作用,通过体外-体内外推(IV-IVE)预测REG与经过UGT1A1代谢消除药物共服引发药物-药物相互作用(DDI)的风险。以混合人肝微粒体(HLM)及重组人源UGTs作为酶源,4-甲基伞形酮(4-MU)作为UGTs的非特异性探针底物,N-(3-羧丙基)-4-羟基-1,8-萘酰亚胺(NCHN)和N-(正丁基)-4-(4-羟苯基)-1,8-萘酰亚胺(NPHN)作为UGT1A1的特异性探针底物,三氟拉嗪(TFP)作为UGT1A4的特异性探针底物,评估REG对12种人UGTs的抑制作用。通过非线性回归并拟合曲线求得半数最大抑制浓度(IC_(50)),Lineweaver-Burk和Dixon作图法确定抑制类型,二次作图法求得抑制动力学常数(K_i),并基于体外抑制动力学参数预测了REG抑制UGT1A1所引发DDI的潜在可能性。体外抑制实验表明,REG对UGT1A1、UGT1A7、UGT1A9和UGT2B7具有较强的抑制作用,IC_(50)为0.15~6.6μmol·L~(-1),K_i为0.027~14μmol·L~(-1)。REG可竞争性的抑制UGT1A1催化的4-MU-O-葡糖醛酸化反应及UGT1A1催化的NPHN-O-葡糖醛酸化反应,而非竞争性的抑制UGT1A1催化的NCHN-4-O-葡糖醛酸化反应,对UGT1A7、UGT1A9和UGT2B7催化的4-MU-O-葡糖醛酸化反应呈现混合型的抑制类型。口服治疗剂量的REG(160 mg·d~(-1))可导致UGT1A1代表性底物NPHN和NCHN的AUC分别增加101%~302%和13%~109%。结果提示,REG与主要经UGT1A1代谢的底物药物联合应用时,可通过强效抑制UGT1A1进而影响其在机体内的代谢清除,在临床使用过程中需要密切关注。
[Abstract]:The inhibitory effects of regorafenibl reg on 12 human uridine diphosphate uronic acid transferases (UGTs) were investigated by using human liver microsomes and recombinant human metabolic enzymes in vitro. In vitro and in vivo extrapolation IV-IVE was used to predict the risk of REG and drug initiation drug interaction through UGT1A1 metabolism. The mixture of human liver microsomes and recombinant human UGTs as enzyme source was used as UGTs. NCHN and N-NCHN were used as specific probe substrates for UGT1A1. Trifluoperazine (TFP) was used as a specific probe substrate of UGT1A4 to evaluate the inhibitory effect of REG on 12 kinds of human UGTs. By nonlinear regression and fitting curve, the inhibition types were determined by IC50 maximum inhibitory concentration (M50), Lineweaver-Burk and Dixon. The inhibition kinetic constant was obtained by secondary mapping method, and the potential possibility of DDI induced by REG inhibiting UGT1A1 was predicted based on in vitro inhibition kinetic parameters. The inhibitory effect of REG on UGT1A1, UGT1A7, UGT1A9 and UGT2B7 was 0.156.6 渭 mol 路L ~ (-1) and 0.156.6 渭 mol 路L ~ (-1), respectively. It was found that 0.027 渭 mol 路L ~ (-1) 路L ~ (-1) mol 路L ~ (-1) 路Reg could competitively inhibit 4-MU-O- glucuronation catalyzed by UGT1A1 and NPHN-O- glucuronation catalyzed by UGT1A1. The non-competitive inhibition of NCHN-4-Oglucuronation catalyzed by UGT1A1, The inhibition of 4-MU-O- glucuronation catalyzed by UGT1A7 and UGT2B7 was of a mixed type. The oral dose of REG(160 mg 路danzl) resulted in the increase of AUC of UGT1A1 substrates NPHN and NCHN by 101% and 109%, respectively. The results suggested that both UGT1A1 substrates NPHN and the base metabolized mainly by UGT1A1 were increased by 101 2% and 10 9%, respectively. When the drug is used in combination, The metabolic clearance of UGT1A1 can be influenced by the strong inhibition of UGT1A1, which should be paid close attention to during clinical use.
【作者单位】：石河子大学药学院新疆植物药资源利用教育部重点实验室;上海中医药大学;
【基金】：国家自然科学基金资助项目(81260627,81660641) 新疆生产建设兵团科技攻关及成果转化计划(2016AD008) 八师石河子市科技计划项目(2016HZ32)
【分类号】：R96

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