本文選題：瑞格非尼　切入點(diǎn)：尿苷二磷酸葡糖醛酸轉(zhuǎn)移酶　出處：《藥學(xué)學(xué)報(bào)》2017年11期 　論文類型：期刊論文

【摘要】：應(yīng)用體外人肝微粒體及重組人源代謝酶孵育體系考察了瑞格非尼(regorafenib,REG)對(duì)12種人尿苷二磷酸葡糖醛酸轉(zhuǎn)移酶(UGTs)的抑制作用,通過(guò)體外-體內(nèi)外推(IV-IVE)預(yù)測(cè)REG與經(jīng)過(guò)UGT1A1代謝消除藥物共服引發(fā)藥物-藥物相互作用(DDI)的風(fēng)險(xiǎn)。以混合人肝微粒體(HLM)及重組人源UGTs作為酶源,4-甲基傘形酮(4-MU)作為UGTs的非特異性探針底物,N-(3-羧丙基)-4-羥基-1,8-萘酰亞胺(NCHN)和N-(正丁基)-4-(4-羥苯基)-1,8-萘酰亞胺(NPHN)作為UGT1A1的特異性探針底物,三氟拉嗪(TFP)作為UGT1A4的特異性探針底物,評(píng)估REG對(duì)12種人UGTs的抑制作用。通過(guò)非線性回歸并擬合曲線求得半數(shù)最大抑制濃度(IC_(50)),Lineweaver-Burk和Dixon作圖法確定抑制類型,二次作圖法求得抑制動(dòng)力學(xué)常數(shù)(K_i),并基于體外抑制動(dòng)力學(xué)參數(shù)預(yù)測(cè)了REG抑制UGT1A1所引發(fā)DDI的潛在可能性。體外抑制實(shí)驗(yàn)表明,REG對(duì)UGT1A1、UGT1A7、UGT1A9和UGT2B7具有較強(qiáng)的抑制作用,IC_(50)為0.15~6.6μmol·L~(-1),K_i為0.027~14μmol·L~(-1)。REG可競(jìng)爭(zhēng)性的抑制UGT1A1催化的4-MU-O-葡糖醛酸化反應(yīng)及UGT1A1催化的NPHN-O-葡糖醛酸化反應(yīng),而非競(jìng)爭(zhēng)性的抑制UGT1A1催化的NCHN-4-O-葡糖醛酸化反應(yīng),對(duì)UGT1A7、UGT1A9和UGT2B7催化的4-MU-O-葡糖醛酸化反應(yīng)呈現(xiàn)混合型的抑制類型�？诜委焺┝康腞EG(160 mg·d~(-1))可導(dǎo)致UGT1A1代表性底物NPHN和NCHN的AUC分別增加101%~302%和13%~109%。結(jié)果提示,REG與主要經(jīng)UGT1A1代謝的底物藥物聯(lián)合應(yīng)用時(shí),可通過(guò)強(qiáng)效抑制UGT1A1進(jìn)而影響其在機(jī)體內(nèi)的代謝清除,在臨床使用過(guò)程中需要密切關(guān)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.
【作者單位】： 石河子大學(xué)藥學(xué)院新疆植物藥資源利用教育部重點(diǎn)實(shí)驗(yàn)室;上海中醫(yī)藥大學(xué);
【基金】：國(guó)家自然科學(xué)基金資助項(xiàng)目(81260627,81660641) 新疆生產(chǎn)建設(shè)兵團(tuán)科技攻關(guān)及成果轉(zhuǎn)化計(jì)劃(2016AD008) 八師石河子市科技計(jì)劃項(xiàng)目(2016HZ32)
【分類號(hào)】：R96

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本文編號(hào)：1596099