本文關(guān)鍵詞： 靈芝 靈芝酸A 代謝產(chǎn)物 藥代動(dòng)力學(xué) 轉(zhuǎn)運(yùn)機(jī)制 藥物相互作用　出處：《北京協(xié)和醫(yī)學(xué)院》2017年博士論文　論文類型：學(xué)位論文

【摘要】：靈芝是擔(dān)子菌綱多孔菌科靈芝屬真菌赤芝(Ganoderma lucidum).和紫芝(Ganoderma sinense)的子實(shí)體,靈芝三萜和多糖是靈芝的兩種主要藥理活性組分。靈芝酸A(Ganodericacid A,GAA)是靈芝中含量最為豐富的三萜酸之一,普遍存在于靈芝屬植物中。研究報(bào)道顯示,GAA具有鎮(zhèn)痛、抗氧化、肝保護(hù)和抗癌等藥理活性。作為靈芝的主要活性成分,GAA單體的代謝、體內(nèi)藥代動(dòng)力學(xué)特性和生物利用度仍鮮有報(bào)道。靈芝及其制劑在臨床及日常保健中被廣泛應(yīng)用,常與其他處方藥物同時(shí)使用,其是否會(huì)和其他藥物發(fā)生藥物相互作用仍然缺乏相關(guān)的研究。本文以靈芝酸A為研究對(duì)象,從整體動(dòng)物及細(xì)胞水平探討靈芝三萜在體內(nèi)的藥代動(dòng)力學(xué)過程及吸收轉(zhuǎn)運(yùn)機(jī)制;以靈芝提取物為研究對(duì)象,考察靈芝是否存在基于外排轉(zhuǎn)運(yùn)體和細(xì)胞色素P450(CYP450)酶的潛在藥物相互作用,為靈芝的合理應(yīng)用和新藥研發(fā)提供依據(jù)。本論文完成的研究工作主要有以下幾個(gè)方面:1.GAA代謝產(chǎn)物及代謝途徑研究采用HPLC-DAD-MS/MS技術(shù),首次鑒定了 GAA的代謝產(chǎn)物,研究了其主要代謝產(chǎn)物的酶動(dòng)力學(xué)特性。對(duì)靜脈給予大鼠GAA后采集到的生物樣品、以及GAA在大鼠和人肝微粒體孵育體系中的代謝產(chǎn)物進(jìn)行鑒定,并對(duì)其主要代謝產(chǎn)物的酶動(dòng)力學(xué)特性進(jìn)行考察。從大鼠膽汁、血漿和尿液中共檢測(cè)鑒定了 37種代謝物;從體外大鼠肝微粒體(RLMs)孵育體系和人肝微粒體(HLMs)孵育體系中分別鑒定了與大鼠體內(nèi)相同的9和7種代謝物。研究提示GAA在人和大鼠體內(nèi)的代謝途徑具有相似性。GAA可以發(fā)生氧化還原羥基化的Ⅰ相代謝和葡萄糖醛酸化磺酸化的Ⅱ相代謝反應(yīng),其主要代謝位點(diǎn)為3、7、11、15、23位的羰基或羥基基團(tuán)和12、20、28(29)位的碳原子。GAA的還原代謝產(chǎn)物在RLMs中的生成速率遠(yuǎn)大于在HLMs中,且均由CYP3A參與代謝。2.GAA及其代謝產(chǎn)物體內(nèi)藥代動(dòng)力學(xué)研究首先建立了靈敏的用于測(cè)定大鼠血漿、膽汁、尿液和腦微透析液中GAA濃度的UFLC-MS/MS分析方法。方法學(xué)考察顯示,該方法線性良好、靈敏可靠,具有低的檢測(cè)限(0.25 nmol/L)和定量限(2.00 nmol/L),精密度、準(zhǔn)確度、萃取回收率、穩(wěn)定性等均能滿足生物樣品分析要求。用所建立的分析方法研究GAA及其主要代謝物靈芝酸C2(C1)、7β,11,15-trihydroxy-3,23-dioxo-lanost-8-en-26-oic acid(C2)、11,15-dihydroxy-3,7,23-trioxo-lanost-8-en-26-oicacid(C3)和靈芝酸B(C4)在大鼠體內(nèi)藥代動(dòng)力學(xué)特性。代謝物濃度以GAA標(biāo)準(zhǔn)曲線進(jìn)行定量。靜脈給予GAA(20mg/kg)后,原型藥在體內(nèi)逐漸消除,同時(shí)生成了豐富的代謝物C1-C4。各代謝物在5 min左右均達(dá)到Cmax值,分別為2.61、0.17、2.84和0.51 μmol/L,且C1、C2、C4在3-6h左右有明顯的重吸收峰。GAA 及其代謝物 C1-C4 的 t1/2 分別為 2.40、13.08、12.35、2.16 和 2.79h,并主要從膽汁中排出,0-24 h在膽汁中的累積排泄率分別為給藥劑量的21.37%、18.02%、2.22%、2.33%和0.70%。而GAA在尿液中的累積排泄率僅為2.59%,代謝物C1-C4的累積排泄率之和為0.076%�？诜o藥(20mg/kg)后,GAA原型藥和四個(gè)代謝物C1-C4在10-40 min出現(xiàn)第一個(gè)血藥濃度峰值,且在6-8 h左右均出現(xiàn)重吸收峰。GAA的口服生物利用度為8.68%。靜脈給藥方式下,GAA可快速通過血腦屏障(Tmax,0.25 h)進(jìn)入腦組織,其血腦屏障透過率為2.96%,在腦透析液中未檢測(cè)到其代謝物C1-C4。3.GAA腸道吸收轉(zhuǎn)運(yùn)機(jī)制研究采用Caco-2細(xì)胞模型,以UFLC-MS/MS分析方法首次研究了 GAA的腸吸收轉(zhuǎn)運(yùn)機(jī)制。結(jié)果表明,GAA在不同濃度(25、50、100 μg/mL)下從腸腔側(cè)(AP)到基底側(cè)(BL)和從BL側(cè)到AP側(cè)的通透量隨濃度和時(shí)間的增加而相應(yīng)增加,表觀滲透系數(shù)PappA→B為(4.30-4.99)×10-7cm/s,Papp B→A為(33.52-37.77)×10-7cm/s,外排率為 6.72-8.79。在 P-糖蛋白(P-gp)抑制劑維拉帕米,多藥耐藥蛋白(MRP)抑制劑MK571和乳腺癌耐藥蛋白(BCRP)抑制劑潘生丁的干預(yù)下,GAA的PappA→B值分別升高至5.79×10-7、12.14×10-7和4.62×10-7cm/s,PappB→A值分別降低至 30.17×10-7、23.55×10-7和 25.57×10-7cm/s,外排顯著降低。提示P-gp、MRP和BCRP均參與GAA的外排轉(zhuǎn)運(yùn),這可能是GAA 口服生物利用度低的主要原因。4.基于外排轉(zhuǎn)運(yùn)體的靈芝潛在藥物相互作用研究通過Caco-2細(xì)胞攝取和跨膜轉(zhuǎn)運(yùn)實(shí)驗(yàn),研究靈芝(Ganoderma lucidum)提取物及單體成分GAA對(duì)外排轉(zhuǎn)運(yùn)體P-gp、MRP和BCRP功能的影響。細(xì)胞攝取實(shí)驗(yàn)結(jié)果顯示,靈芝總提物(GLE)和靈芝三萜提取物(GLT)在濃度為100 μg/mL時(shí),使P-gp底物羅丹明123(Rho)和MRP底物鈣黃綠素(Cal)的攝取量顯著增加,對(duì)P-gp和MRP功能表現(xiàn)出抑制作用;使BCRP的底物Hoechst 33342(Hoe)的攝取量顯著降低,對(duì)BCRP功能表現(xiàn)出誘導(dǎo)作用。靈芝多糖提取物(GLP)在實(shí)驗(yàn)濃度下則對(duì)P-gp和MRP功能無顯著影響,在濃度為100 μg/mL時(shí)對(duì)BCRP表現(xiàn)出誘導(dǎo)作用。GAA在實(shí)驗(yàn)濃度下對(duì)P-gp、MRP和BCRP功能均無顯著影響。Caco-2細(xì)胞轉(zhuǎn)運(yùn)模型實(shí)驗(yàn)中,用不同濃度GLE和GLT干預(yù)Rho的跨膜轉(zhuǎn)運(yùn)時(shí),Rho從AP到BL的通透量和Papp a→b值均顯著增加,從BL到AP的通透量和PappB→A值均顯著降低,且表現(xiàn)出劑量依賴性,提示GLE和GLT可以抑制P-gp的外排作用。用不同濃度GLE和GLT干預(yù)Cal的外排時(shí),Cal在AP側(cè)的通透量表現(xiàn)出不同程度的降低,在Caco-2細(xì)胞單層膜中的累積量表現(xiàn)出不同程度的增加,提示GLE和GLT可以抑制MRP的外排作用。靈芝三萜是靈芝發(fā)揮外排轉(zhuǎn)運(yùn)體抑制作用的主要活性成分。提示靈芝在與外排轉(zhuǎn)運(yùn)體底物藥物合并使用時(shí),可能存在藥物相互作用風(fēng)險(xiǎn)。5.基于CYP450酶的靈芝潛在藥物相互作用研究選擇臨床常用藥物非那西丁、奧美拉唑、右美沙芬、睪酮、甲苯磺丁脲、氯唑沙宗分別作為CYP1A2、CYP2C19、CYP2D6、CYP3A4、CYP2C9 和 CYP2E1 的探針底物,結(jié)合 UFLC-MS/MS 技術(shù)對(duì)底物代謝物進(jìn)行檢測(cè),以Cocktail探針底物肝微粒體代謝反應(yīng)體外評(píng)價(jià)方法,對(duì)靈芝提取物和其主要成分GAA的CYP450酶抑制活性進(jìn)行研究。結(jié)果顯示,在HLMs中,GLE對(duì)CYP2C19、2D6、3A4和2C9表現(xiàn)出微弱的抑制作用,IC50值分別為131.2、164.4、150.5和142.2 μg/mL。GLT的抑制作用略強(qiáng)于GLE,IC50值分別為102.5、116.1、136.4和82.2μg/mL。GLP對(duì)6種CYP450酶抑制作用均不明顯。在RLMs中,GLT對(duì)CYP2C9表現(xiàn)出微弱的抑制作用,IC50值為163.1μg/mL,而對(duì)其他酶活性無影響;GLE和GLP對(duì)6種CYP450酶均不產(chǎn)生抑制作用。單體成分GAA在1-50 μmol/L的濃度范圍內(nèi)對(duì)HLMs和RLMs中的CYP450酶均無抑制作用。
[Abstract]:Ganoderma lucidum is basidiomycetes Polyporaceae fungi of the genus Ganoderma lucidum Ganoderma lucidum (Ganoderma lucidum). (Ganoderma sinense) and Ganoderma fruiting bodies of Ganoderma lucidum three terpene and polysaccharide are two main pharmacological active components of Ganoderma lucidum. Ganoderic acid A (Ganodericacid A GAA) is one of three triterpene acids in Ganoderma lucidum rich most the content exists in the ganoderma genus. Research reports show that GAA has analgesic, antioxidant, hepatoprotective and anticancer activity of Ganoderma lucidum. As the main component, the metabolism of GAA monomer, pharmacokinetic characteristics and bioavailability of Ganoderma lucidum and its preparation is still rarely reported. It is widely applied in clinical and daily health care, often used in conjunction with other prescription drugs, it will occur and other drug drug interactions is still a lack of relevant research. In this paper, ganoderic acid A as the research object, from the whole animal and cellular level of three terpene in Ganoderma lucidum The in vivo pharmacokinetics and mechanism of absorption and transport; the Ganoderma lucidum extract of Ganoderma lucidum as the research object, the existence of efflux transporter and cytochrome P450 (CYP450) based on the interaction of the enzyme for potential drugs, the rational use of Ganoderma lucidum and new drug development. Provide the basis for the research in this thesis mainly includes the following aspects: study metabolites and metabolic pathways of 1.GAA using HPLC-DAD-MS/MS technology, first identified metabolites of GAA, enzyme kinetics of its main metabolites. The intravenous administration of rat GAA after collected biological samples, and GAA in rat and human liver microsomes incubated with metabolites in the system were identified, and the enzyme dynamic characteristics of the main metabolites were investigated. From rat bile, plasma and urine were detected and identified 37 metabolites from rat liver microsomes in vitro; (RLMs). The education system (HLMs) and human liver microsomes incubation system were identified with the rats the same 9 and 7 metabolites. Studies suggest that GAA metabolic pathways in rat and human body is similar to that of.GAA can undergo redox hydroxylation phase I metabolism and glucuronidation of sulfonated phase II metabolism the main metabolic reaction sites for 3,7,11,15,23 bits of the carbonyl or hydroxyl groups and 12,20,28 (29) generation rate reduction metabolites a carbon atom of.GAA in RLMs is much larger than that in HLMs, and CYP3A is involved in the metabolism of.2.GAA and its metabolic products in vitro in pharmacokinetic studies was first established for the determination of high sensitive the concentration of GAA in plasma, bile, urine and brain Microdialysate UFLC-MS/MS analysis method. The influences of display method, this method has good linearity, sensitivity and reliability, has a low detection limit (0.25 nmol/L) and limit of quantification (2 nmol/L) , precision, accuracy, recovery, stability can meet the requirements of biological sample analysis. By analyzing the research of GAA and its metabolites ganoderic acid C2 (C1), 7 beta, 11,15-trihydroxy-3,23-dioxo-lanost-8-en-26-oic acid (C2), 11,15-dihydroxy-3,7,23-trioxo-lanost-8-en-26-oicacid (C3) and ganoderic acid B (C4) in vivo in rats pharmacokinetic characteristics. Metabolite concentrations were quantified using the GAA standard curve. Intravenous GAA (20mg/kg), the prototype drug gradually eliminate the in vivo metabolite of C1-C4. rich metabolite reached Cmax value at about 5 min is obtained at the same time, respectively 2.61,0.17,2.84 and 0.51 mol/L, and C1, C2, C4 have obvious weight the absorption peak of.GAA and its metabolite C1-C4 t1/2 were 2.40,13.08,12.35,2.16 and 2.79h in 3-6h, and mainly from the bile discharge, 0-24 h in the bile of the cumulative excretion rate Don't let the dosage of 21.37%, 18.02%, 2.22%, 2.33% and 0.70%. and GAA cumulative excretion in the urine was only 2.59%, the cumulative excretion of metabolites C1-C4 and oral administration of 0.076%. (20mg/kg), GAA drug prototype and four metabolites C1-C4 first peak blood concentration in 10-40 min and, at about 6-8 h appeared heavy absorption peak of.GAA by the oral bioavailability is 8.68%. intravenous administration, GAA can quickly through the blood-brain barrier (Tmax, 0.25 h) into the brain tissue, the blood brain barrier permeability is 2.96%, in brain dialysate was not detected in the metabolism of C1-C4.3.GAA study on intestinal absorption mechanism using Caco-2 cell model, GAA method was studied for the first time the intestinal absorption mechanism by UFLC-MS/MS analysis. The results showed that GAA in different concentration (25,50100 g/mL) from the intestinal lumen to the basolateral side (AP) (BL) and permeability from BL side to side with the concentration of AP Increased and time and the corresponding increase in the apparent permeability coefficient PappA, B (4.30-4.99) * 10-7cm/s, Papp B, A (33.52-37.77) * 10-7cm/s, the efflux rate of 6.72-8.79. in the P- glycoprotein (P-gp) inhibitor Vera Pammy, multidrug resistance protein (MRP) inhibitor MK571 and breast cancer resistance protein (BCRP under the intervention of Pan Shengding) inhibitor, GAA PappA, B values were increased to 5.79 * 10-7,12.14 * 10-7 and 4.62 * 10-7cm/s, PappB, A values were reduced to 30.17 * 10-7,23.55 * 10-7 and 25.57 * 10-7cm/s, suggesting that P-gp efflux was significantly reduced. MRP, and BCRP were involved in GAA efflux transporters, this GAA may be the main reason of low oral bioavailability of Ganoderma lucidum.4. potential drug efflux transporter based on the interaction between the Caco-2 cell uptake and the transmembrane transport experiments of Ganoderma lucidum (Ganoderma lucidum) extracts and monomer composition of GAA efflux transporter P-gp, MRP The influence and the function of BCRP. Cell uptake results showed that Ganoderma lucidum extract (GLE) and three (GLT) of Ganoderma lucidum terpenoid extract at the concentration of 100 g/mL, the P-gp substrate 123 (Rho) and Luo Danming MRP (Cal) substrate calcein uptake increased significantly, the P-gp and MRP functions the inhibitory effect of the BCRP Hoechst 33342 substrate; (Hoe) the intake significantly decreased, the function of BCRP showed induction effect. Polysaccharide extracts of Ganoderma (GLP) at the concentration of P-gp and MRP had no significant effect on the concentration of 100 g/mL of BCRP showed the induction of.GAA in the concentration of P-gp, MRP and BCRP have no significant effect on.Caco-2 cells in model experiment, with the transmembrane transport of different concentrations of GLE and GLT intervention Rho, Rho from AP to BL and Papp a, B permeability values were significantly increased, from BL to AP and PappB, A transparent the values were significantly decreased, and the Showed dose dependent, suggesting that GLE and GLT can inhibit the activity of P-gp. With different concentrations of GLE and GLT intervention Cal efflux, Cal permeability in AP side showed different degrees of reduction, accumulation in Caco-2 cell monolayer showed different degrees of increase, in GLE and GLT can suppress the activity of MRP. The three is the main active ingredient of Ganoderma lucidum triterpenoids inhibition effect of Ganoderma lucidum play efflux transporter. In Ganoderma lucidum and efflux transporter substrates with drug use, there may be a risk of drug interactions.5. potential drug omeprazole Ganoderma CYP450 enzyme interaction of clinically used drugs acetophenetidin based on that, dextromethorphan, testosterone, tolbutamide chlorzoxazone, respectively as CYP1A2, CYP2C19, CYP2D6, CYP3A4, CYP2C9 and CYP2E1 probe substrate, combined with the technology of UFLC-MS/MS substrate metabolism into line with detection. Cocktail probe substrate liver microsomal metabolism reaction in vitro evaluation methods, CYP450 enzyme of Ganoderma lucidum extract and its main component of GAA inhibitory activity were studied. The results showed that in HLMs, GLE of CYP2C19,2D6,3A4 and 2C9 showed weak inhibition, IC50 was inhibition of 131.2164.4150.5 and 142.2 g/mL.GLT is stronger than GLE, IC50 the values were 102.5116.1136.4 and 82.2 g/mL.GLP to 6 CYP450 enzyme inhibition was not obvious. In RLMs, GLT showed a weak inhibitory effect on CYP2C9, IC50 value is 163.1 g/mL, but have no effect on other enzyme activity; GLE and GLP of 6 kinds of CYP450 enzymes was not inhibited. Monomer the component GAA in the concentration range of 1-50 mol/L CYP450 enzyme on HLMs and RLMs were not inhibited.

【學(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類號(hào)】：R285.5

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