本文關(guān)鍵詞：溶栓候選藥物FGFC1藥物代謝動(dòng)力學(xué)特性的研究　出處：《上海海洋大學(xué)》2016年碩士論文　論文類型：學(xué)位論文

  更多相關(guān)文章： FGFC1 比格犬 藥物代謝動(dòng)力學(xué) 組織分布 CACO-2細(xì)胞模型 CYP450

【摘要】：隨著氣候變暖、資源匱乏和人口增多等變化,心腦血管疾病(cardiovascular and cerebrovascular diseases,CCVD)、癌癥、病毒性感染等難治性疾病嚴(yán)重威脅到人類的健康和生存,尤其是心腦血管疾病藥物已經(jīng)成為世界各國(guó)藥物科學(xué)家研究的熱點(diǎn),發(fā)現(xiàn)新型海洋藥物有可能徹底治療難治性疾病逐漸成為社會(huì)共識(shí)。論文基于海洋真菌長(zhǎng)孢葡萄穗霉菌FG216(Stachybotrys longispora FG216)代謝產(chǎn)物溶栓候選藥物FGFC1的結(jié)構(gòu)和纖溶活性的確認(rèn),研究了比格犬體內(nèi)的藥物代謝動(dòng)力學(xué)特性和組織分布規(guī)律,探索了FGFC1在CACO-2細(xì)胞模型中的吸收轉(zhuǎn)運(yùn)特性及其對(duì)肝藥酶活性的影響,在小分子溶栓海洋新藥的開發(fā)上具有應(yīng)用價(jià)值,在新型溶栓理論的建立上具有科學(xué)意義。第一章綜述了國(guó)內(nèi)外溶栓藥物的研究現(xiàn)狀,同時(shí)介紹了以同位素標(biāo)記法和代謝組學(xué)為代表的體內(nèi)藥物代謝動(dòng)力學(xué)以及CACO-2細(xì)胞模型和肝微粒體酶為代表的體外藥物代謝動(dòng)力學(xué)。第二章是溶栓候選藥物FGFC1的結(jié)構(gòu)和纖溶活性的確認(rèn)。溶栓候選藥物FGFC1結(jié)構(gòu)通過(guò)1H NMR,13C NMR等光譜被確定為2,5-二((2-(2,4,-二甲基-2,4-二烯)壬基)-(2-甲基-3-羥基)-吡喃并(5-羥基)-異吲哚酮基)-戊酸。通過(guò)Glu-纖維蛋白溶酶原和Lys-纖維蛋白溶酶原測(cè)量體外活性,結(jié)果表明0.1-0.4 mmol/L FGFC1能提高纖維蛋白溶酶活性2.05-11.44倍。FITC-纖維蛋白原降解實(shí)驗(yàn)表明FGFC1通過(guò)激活纖維蛋白溶酶原的活性來(lái)發(fā)揮作用。劑量為10 mg/kg的FGFC1能降解大鼠急性肺血栓。第三章是研究FGFC1在比格犬體內(nèi)的藥物代謝動(dòng)力學(xué)和組織分布。比格犬靜脈注射7.5 mg·kg-1、5.0 mg·kg-1和2.5mg·kg-1三種劑量的FGFC1,在不同的時(shí)間點(diǎn)取血,用HPLC檢測(cè)血漿和組織器官中FGFC1的濃度并通過(guò)PKslover軟件計(jì)算其藥物代謝動(dòng)力學(xué)參數(shù),統(tǒng)計(jì)組織分布規(guī)律。藥物代謝動(dòng)力學(xué)實(shí)驗(yàn)結(jié)果表明,FGFC1在比格犬體內(nèi)消除半衰期(t1/2β)分別為49.035±2.171,48.422±2.113和48.811±2.372 min;達(dá)峰濃度Cmax分別為56.48±6.23、48.63±5.53和13.64±2.76μg?mL-1;機(jī)體總消除率(CL)分別為0.0062±0.0004、0.0071±0.0008和0.0092±0.0006(L·min-1·kg-1);平均保留時(shí)間(MRT)分別為28.17±1.16、26.23±0.35和28.66±0.84min。心、肝、脾、肺、腎、腦、肌肉、睪丸、腸、膽汁、糞便和尿液中均發(fā)現(xiàn)FGFC1原型藥,其中肝臟和膽汁中的含量最高,其中肝臟和膽汁中含量較高,肺、腎臟、脾臟、胃糞便、尿液中含量中等,其余含量一般。表明FGFC1在全身各處都能檢測(cè)出FGFC1,說(shuō)明FGFC1具有良好的組織分布,對(duì)達(dá)到全身各個(gè)病灶第四章是研究FGFC1吸收和轉(zhuǎn)運(yùn)特性。通過(guò)LC/MS/MS技術(shù)檢測(cè)FGFC1在CACO-2細(xì)胞模型的外排比、總回收率和表觀滲透系數(shù)。結(jié)果顯示AP→BL方向和BL→AP方向的Papp值均小于2.5×10-6 cm·s-1,從AP→BL側(cè)的Papp AP-BL值和BL→AP側(cè)的Papp BL-AP值沒(méi)有統(tǒng)計(jì)學(xué)意義上的差異,且其外排比值均接近1.5,說(shuō)明FGFC1在CACO-2細(xì)胞模型中以被動(dòng)擴(kuò)散為主�？诜o藥FGFC1可能吸收不完全,使用靜脈給藥被認(rèn)為能增強(qiáng)其生物利用度。第五章是研究FGFC1對(duì)大鼠肝微粒體酶的影響。在大鼠肝微粒體孵育體系加入探針底物非那西丁、咪達(dá)唑侖及氯唑沙宗來(lái)反映FGFC1對(duì)大鼠肝微粒體酶細(xì)胞色素CYP450(Cytochrome P450 proteins,CYP450)的影響,同時(shí),還觀察了在連續(xù)給藥下大鼠的肝臟組織形態(tài)學(xué)和大鼠與大白兔的心電圖參數(shù)。實(shí)驗(yàn)結(jié)果顯示,FGFC1在41.6 mg·kg-1·d-1的高劑量下能顯著誘導(dǎo)CYP3A4,還能帶來(lái)肝竇擴(kuò)張和細(xì)胞腫大等形態(tài)學(xué)上的變化。大白鼠和大白兔的處理劑量為7.5 mg·kg-1、5.0mg·kg-1和2.5mg·kg-1的FGFC1對(duì)其P波、PR間期、QRS波群、ST-T間期以及心率等心電圖參數(shù)沒(méi)有顯著影響。FGFC1在連續(xù)高劑量給藥下可能是一種潛在的CYP3A4誘導(dǎo)劑,同時(shí)FGFC1的長(zhǎng)期給藥可能對(duì)肝臟產(chǎn)生一定的影響,這需要以后繼續(xù)進(jìn)行研究。溶栓候選藥物FGFC1的結(jié)構(gòu)經(jīng)NMR和MS等被確認(rèn)為吲哚類化合物的2,5-二((2-(2,4,-二甲基-2,4-二烯)壬基)-(2-甲基-3-羥基)-吡喃并(5-羥基)-異吲哚酮基)-戊酸,纖溶活性被體內(nèi)外實(shí)驗(yàn)所證實(shí)。FGFC1比格犬體內(nèi)的半衰期為48-49min,屬于二室模型,廣泛分布于個(gè)組織和器官,主要分布于肝臟和膽汁。FGFC1從外排比、總回收率和表觀滲透系數(shù)等體現(xiàn)出以被動(dòng)擴(kuò)散為主,高劑量FGFC1能顯著誘導(dǎo)肝藥酶CYP3A4并且還能帶來(lái)肝竇擴(kuò)張和細(xì)胞腫大等形態(tài)學(xué)上的變化。但不會(huì)得心臟功能產(chǎn)生影響。
[Abstract]:With climate warming, resources shortage and the increasing population changes, cardiovascular and cerebrovascular diseases (cardiovascular and, cerebrovascular diseases, CCVD), cancer, viral infections and other refractory disease is a serious threat to human health and survival, especially of drugs for cardiovascular and cerebrovascular diseases has become the focus of pharmaceutical scientists around the world, find new marine drugs may complete the treatment of refractory disease has gradually become a social consensus. Based on the marine fungus spore fungus Stachybotrys FG216 long (Stachybotrys longispora FG216) fiber structure and metabolites of thrombolytic drug candidates FGFC1 dissolution activity confirmed of beagle dogs pharmacokinetic characteristics and tissue distribution, to explore the FGFC1 absorption and transportation characteristics in CACO-2 cell model and its effect on the activity of liver enzyme, in small molecule drug development on marine thrombolysis should have With the value of scientific significance in the establishment of new thrombolytic theory. The first chapter reviews the domestic and foreign research status of thrombolytic drugs, and introduces the in vitro pharmacokinetics by isotope labeling method and metabolomics pharmacokinetics as the representative and the CACO-2 cell model and liver microsomal enzyme as the representative of the second chapter is confirmed. The fiber structure and thrombolytic drug candidate FGFC1 fibrinolytic activity. Thrombolytic drug candidate FGFC1 13C NMR structure by 1H NMR spectra was determined to be two 2,5- ((2- (2,4, two - methyl nonyl diene -2,4-) - (2-) -3- hydroxy methyl) - pyrano (5- hydroxy) - isoindolone base) - pentanoic acid by Glu- plasminogen and Lys- plasminogen in vitro activity measurements, the results show that 0.1-0.4 mmol/L FGFC1 can increase the soluble enzyme activity 2.05-11.44 times.FITC- fibrinogen degradation experiment showed that FGFC1 induced by fibrin Live plasminogen activity to play a role. The dose of 10 mg/kg FGFC1 of acute pulmonary embolism in rats. The third chapter is the degradation of FGFC1 in beagle dogs in vivo pharmacokinetics and tissue distribution of beagle dogs. Intravenous injection of 7.5 mg - kg-1,5.0 Mg - kg-1 and 2.5mg - kg-1 three dose of FGFC1. The blood samples were taken at different time points, with the concentration of FGFC1 in plasma and tissue organ detection in HPLC and through the PKslover software to calculate the pharmacokinetic parameters, statistical tissue distribution. The experimental results show that the pharmacokinetics of FGFC1 in beagle dogs, the elimination half-life (t1/2 beta) were 49.035 + 2.171,48.422 + 2.113 and 48.811 + 2.372 min; peak concentration Cmax = 56.48 + 6.23,48.63 + 5.53 and 13.64 + 2.76 G? ML-1; the total elimination rate (CL) were 0.0062 + 0.0004,0.0071 + 0.0008 and 0.0092 + 0.0006 (L min-1 kg-1); the average. Retention time (MRT) were 28.17 + 1.16,26.23 + 0.35 and 28.66 + 0.84min. in heart, liver, spleen, lung, kidney, brain, testis, muscle, intestine, bile, FGFC1 drug prototype were found in the feces and urine, the content of liver and bile in the highest, higher content of liver and bile in the lung the spleen, stomach, kidney, feces, urine content of medium, the general content. The results indicated that FGFC1 can detect FGFC1 in the body, indicating that FGFC1 has good tissue distribution, to achieve the body of each lesion fourth chapter is the research on FGFC1 uptake and transport characteristics. Through the detection of FGFC1 LC/MS/MS in CACO-2 cell model of parallelism the total recovery rate, and the apparent permeability coefficient. The results showed that AP, BL, AP direction and BL direction of the Papp values were less than 2.5 * 10-6 cm s-1, from AP to BL Papp AP-BL and BL side, AP side of the Papp BL-AP value was no significant difference in meaning, and the external value of parallelism Close to 1.5, indicating that FGFC1 is dominated by passive diffusion in CACO-2 cell model. The oral administration of FGFC1 could not completely absorbed, the use of intravenous administration is thought to enhance its bioavailability. The fifth chapter is the research on the influence of FGFC1 on rat liver microsomal enzymes. Education system added to probe substrate phenacetin in rat liver microsomes then, midazolam and chlorazol Sha Zong to reflect on the pigment FGFC1 in rat liver microsome cell CYP450 (Cytochrome P450 proteins, CYP450) effect, at the same time, was also observed in the continuous ECG parameters of liver tissue morphology medicine rats and rats and white rabbits. Experimental results show that high dose of FGFC1 in 41.6 Mg - kg-1 - D-1 could significantly induce CYP3A4, but also bring the changes of hepatic sinus expansion and enlargement of cell morphology. Treatment dose of rats and rabbits was 7.5 mg - kg-1,5.0mg - kg-1 and 2.5mg - kg-1 to FGFC1 The P wave, QRS wave, PR interval, ST-T interval and heart rate did not significantly affect the.FGFC1 ECG parameters in continuous high dose may be a potential inducer of CYP3A4, FGFC1 and the long-term administration may have a certain impact on the liver, the need to continue after thrombolysis in research. The structure of candidate drug FGFC1 by NMR and MS were identified as indole compounds (2,5- two (2- (2,4, two - -2,4- diene nonyl methyl) - (2-) -3- hydroxy methyl (5-) - pyran and hydroxyl) - isoindole ketone) - pentanoic acid, fibrinolytic activity was confirmed by in vitro and in vivo..FGFC1 Beagle half-life is 48-49min, which belongs to the two compartment model, widely distributed in tissues and organs, mainly distributed in liver and bile.FGFC1 from the outer parallelism, the total recovery rate and the apparent permeability coefficient shows by passive diffusion. High dose FGFC1 could significantly induce liver enzymes and CYP3A4 It also brings morphological changes, such as the dilatation of the hepatic sinusoids and the enlargement of the cells, but does not have the effect of the heart function.

【學(xué)位授予單位】：上海海洋大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2016
【分類號(hào)】：R96

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4 童心s，

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