本文選題：酒石酸泰萬菌素 + 口服生物利用度��； 參考：《南京農業(yè)大學》2015年碩士論文

【摘要】：為探討影響酒石酸泰萬菌素口服生物利用度的因素,本研究采用雞肝原代細胞模型、Caco-2細胞模型和小腸灌流模型,體外研究酒石酸泰萬菌素代謝消除和吸收轉運。并通過抑制CYP3A和P-gp,考察其對酒石酸泰萬菌素在AA肉雞體內的藥動學影響。具體分為以下幾個部分:1酒石酸泰萬菌素生物利用度的研究為了研究酒石酸泰萬菌素的口服生物利用度,建立了血漿、培養(yǎng)基和緩沖液中酒石酸泰萬菌素的處理及高效液相(HPLC)色譜分析方法。1日齡的AA肉雞飼喂至28日齡后,挑選20只健康雄性肉雞,分為口服和靜脈給藥兩組,每組10只,分別灌服和靜注10mg·kg-1.b.w的酒石酸泰萬菌素溶液。給藥后24h內,翅下靜脈采血,用HPLC法測定酒石酸泰萬菌素血藥濃度,用3P97藥動學軟件分析藥-時數(shù)據。結果顯示,建立的HPLC方法符合定量檢測要求。肉雞單劑量口服和靜注酒石酸泰萬菌素的藥動學過程符合二室開放模型。口服后血漿中泰萬菌素的藥時曲線下面積(AUC)為0.82μg·mL-1·h,達峰時間(Tmax)0.72h;靜注后血漿中泰萬菌素的藥時曲線下面積(AUC)為6.47μg·mL-1·h。結果表明,酒石酸泰萬菌素口服后,吸收迅速,但口服生物利用度(F)低,僅有12.67%。2影響酒石酸泰萬菌素口服生物利用度部位的定量研究1日齡的AA肉雞飼喂至42日齡后,挑選40只健康雄性肉雞,隨機分為口服給藥組、十二指腸給藥組、門靜脈給藥組和靜脈給藥組,每組10只。肉雞麻醉后,以10 mg·kg-1劑量按以上給藥方式給予酒石酸泰萬菌素溶液。給藥后24 h內,翅下靜脈采血,用HPLC法測定酒石酸泰萬菌素血藥濃度,用3P97藥動學軟件分析藥-時數(shù)據。結果顯示,不同途徑給藥后,酒石酸泰萬菌素的藥動學過程符合二室開放動力學模型。靜脈給藥組的曲線下面積(AUC)顯著高于門靜脈給藥組;靜脈和門靜脈給藥組都顯著高于口服給藥組。結果表明,酒石酸泰萬菌素的口服生物利用度主要受腸道和肝臟影響。腸道影響最大,達87.2%,其次為肝臟,達16.2%。3酒石酸泰萬菌素代謝消除和吸收轉運的體外研究利用肝原代細胞體外代謝模型、Caco-2單層細胞體外轉運模型和腸道灌流模型,分別研究酒石酸泰萬菌素的體外代謝消除和體外吸收轉運。利用肝原代細胞體外代謝模型,以不同濃度的酒石酸泰萬菌素考察代謝消除,并抑制CYP1A和CYP3A活性,考察它們對酒石酸泰萬菌素代謝的影響;運用Caco-2單層細胞體外轉運模型研究酒石酸泰萬菌素吸收特點,同時考察p-gp對其轉運的影響;運用腸道灌流模型,添加EGTA和抑制P-gp,分別對十二指腸、空腸和回腸進行單向灌流,考察酒石酸泰萬菌素吸收的主要腸段和P-gp對酒石酸泰萬菌素轉運的影響。結果顯示,酒石酸泰萬菌素在肝細胞中存在著代謝消除,而且有時間依賴性和濃度依賴性,符合酶促動力學特征。CYP3A被抑制后,酒石酸泰萬菌素代謝消除顯著減慢。Caco-2細胞中,轉運呈現(xiàn)細胞旁轉運和跨細胞轉運并存;EGTA的存在會使轉運系數(shù)增加;存在P-gp介導的外排現(xiàn)象。而在小腸灌流過程中,十二指腸吸收迅速,是主要吸收腸段,吸收方式以跨細胞轉運為主;EGTA的存在難以提高吸收效率,維拉帕米的存在可以顯著降低P-gp介導的外排;各腸段的轉運系數(shù)說明在十二指腸吸收良好,空腸和回腸的吸收較差。結果表明,CYP3A參與了酒石酸泰萬菌素的代謝消除,由它引起的首過效應會使酒石酸泰萬菌素的口服生物利用度降低,另外,腸道的吸收不良、P-gp介導的外排及在腸系膜中的代謝也是酒石酸泰萬菌素口服生物利用度低的原因。4 CYP3A以及P-gp對酒石酸泰萬菌素在AA肉雞體內的藥動學影響1日齡的AA肉雞飼喂至42日齡后,挑選60只健康雄性肉雞,隨機分為酮康唑處理組、維拉帕米處理組以及對照組,每組20只。酮康唑處理組按照60 mg·kg-1.b.w的劑量給動物灌服酮康唑,1天1次,第3天灌藥0.5 h后,按10mg·kg-1.b.w灌服和靜注酒石酸泰萬菌素溶液;其它兩組分別連續(xù)灌服9 mg·kg-1.b.w的維拉帕米和相同體積的生理鹽水,第3天灌藥0.5 h后,按10 mg·kg-1.b.w灌服和靜注酒石酸泰萬菌素溶液。給藥后24 h內,翅下靜脈采血,用HPLC法測定酒石酸泰萬菌素血藥濃度,用3P97藥動學軟件分析藥-時數(shù)據。結果表明,肉雞以單劑量口服和靜注酒石酸泰萬菌素的藥動學過程符合二室開放動力學模型�？诜o藥后對照組的藥-時曲線下面積(AUC)為0 96μg·mL-1·h,表觀清除率(CL/F)為 15.3L·kg-1·h-1;肉雞體內 CYP3A 活性被酮康唑特異性抑制后,血漿中泰萬菌素的藥時曲線下面積上升到1.12 μg·mL-1·h,表觀清除率為14.8 L-kg-1·h-1,均沒有顯著變化;肉雞體內P-gp被維拉帕米特異性抑制后,藥-時曲線下面積為1.29μg·mL-1·h,顯著升高。結果顯示,CYP3A對酒石酸泰萬菌素在AA肉雞體內的代謝消除影響不明顯,而P-gp影響顯著。
[Abstract]:In order to explore the factors affecting the oral bioavailability of tymbiate tartrate, this study used the chicken liver primary cell model, Caco-2 cell model and small intestinal perfusion model to study the metabolism elimination and absorption and transport of tymbiate tartaric acid in vitro. By inhibiting CYP3A and P-gp, the pharmacokinetics of tymbiate tartrate in AA broilers were investigated. The effect is divided into the following parts: 1 study on bioavailability of tybbin tartrate in order to study the oral bioavailability of tybbin tartrate, establish the treatment of plasma, culture medium and buffer solution of tybbin tartaric acid and high performance liquid phase (HPLC) chromatographic analysis method.1 AA broiler fed to 28 days of age to select 20 Only healthy male broilers were divided into two groups: oral and intravenous administration of two groups, 10 rats in each group, respectively, filled with and intravenous infusion of 10mg kg-1.b.w tartaric acid tymbium solution. After the administration, the blood was collected from the inferior winged vein in 24h, and the blood concentration of tymbium tartrate was measured by HPLC method. The data of drug time were analyzed with the 3P97 pharmacokinetic software. The results showed that the established HPLC method conformed to the data. The pharmacokinetics of single dose and intravenous infusion of tymbium tartrate in broilers conformed to the two compartment open model. The area under the curve (AUC) was 0.82 G. ML-1. H, and peak time (Tmax) 0.72h after oral administration of the drug, and the area under the curve (AUC) was 6.47 mu g. ML-1 h. junction in the plasma after intravenous injection. The results showed that after oral administration of tymbium tartrate, the uptake was rapid, but oral bioavailability (F) was low and only 12.67%.2 affected the oral bioavailability of tartrate. 1 day old AA broilers were fed to 42 days of age to select 40 healthy male broilers and randomly divided into oral administration, duodenal administration, portal vein. The drug group and the intravenous administration group were 10 in each group. After the broiler was anaesthetized, the drug was given at the dosage of 10 mg. Kg-1. The blood was collected in the lower wing vein in 24 h after the administration. The blood concentration of tymbium tartrate was measured by HPLC method. The drug time data were analyzed with the 3P97 pharmacokinetic software. The results showed that after different routes were given, tartrate The pharmacokinetic process of tymx was in accordance with the two chamber open kinetic model. The area under the curve (AUC) in the intravenous administration group was significantly higher than that in the portal vein group; the intravenous and portal intravenous administration groups were significantly higher than the oral administration group. The results showed that the oral bioavailability of the tymbin tartrate was mainly influenced by the intestinal and liver. Large, up to 87.2%, followed by liver, metabolism elimination and absorption of 16.2%.3 tartrate metabolism and absorption and transport in vitro studies using liver primary cell metabolism model, Caco-2 monolayer in vitro transport model and intestinal perfusion model, respectively, to study in vitro metabolic elimination and in vitro absorption and transport of tymbiate tartaric acid, respectively. In vitro metabolic model, metabolic elimination was investigated with different concentrations of tymbin tartrate, and the effects of CYP1A and CYP3A activity on the metabolism of tymbiate tartaric acid were investigated. The absorption characteristics of tymbiate tartaric acid were studied by the model of Caco-2 monolayer in vitro transport, and the effects of P-gp on its transport were investigated at the same time. EGTA and P-gp were added to the duodenum, jejunum and ileum for unidirectional perfusion, and the effects of the main intestinal segments and P-gp on tartaric acid tymbium transport were investigated. The results showed that the metabolic elimination of tymbium tartrate in the hepatocytes was consistent with the time dependence and concentration dependence. After the enzyme kinetic characteristic.CYP3A was inhibited, the metabolism of tymx tartrate was eliminated significantly in.Caco-2 cells, and the transport of paracellular transport and cross cell transport coexisted; the presence of EGTA increased the transport coefficient and the P-gp mediated exclusion. The duodenum absorbed rapidly in the intestinal perfusion process, which was the main absorption of the intestinal segment. The absorption mode was mainly transcellular transport, and the presence of EGTA was difficult to improve the absorption efficiency. The existence of Vera Pammy could significantly reduce the P-gp mediated outer row. The transport coefficient of the intestinal segments showed that the absorption of the duodenum was good and the absorption of the jejunum and the ileum was poor. The results showed that the metabolism of CYP3A ginseng and tymbium tartrate was eliminated and caused by it. The first over effect will reduce the oral bioavailability of tybb, in addition, the intestinal malabsorption, the P-gp mediated outer row and the metabolism in the mesentery are also the cause of the low bioavailability of tybon tartaric acid,.4 CYP3A and P-gp on the pharmacokinetics of tybbin tartrate in AA broilers at 1 days of age AA After feeding the broiler to 42 days old, 60 healthy male broilers were selected and randomly divided into ketoconazole treatment group, Vera Pammy treatment group and control group, 20 rats in each group. Ketoconazole treatment group was given ketoconazole in accordance with 60 mg kg-1.b.w dose. 1 days 1 times, third days after irrigation 0.5 h, infusion of 10mg. Kg-1.b.w and intravenous tartaric acid tymbin solution The other two groups were given 9 mg / kg-1.b.w of Vera Pammy and the same volume of normal saline respectively. After third days of 0.5 h irrigation, they were filled with 10 mg kg-1.b.w and filled with tartaric acid tymbin solution. The blood was collected in the lower winged vein in 24 h after the administration, and the concentration of tymbium tartrate was measured by HPLC method, and the drug was analyzed with 3P97 pharmacokinetic software. The results showed that the pharmacokinetic process of broiler with a single dose of oral and static injection of tymbium tartrate was in accordance with the two compartment open kinetic model. The area under the drug time curve (AUC) of the control group was 096 G. ML-1. H after oral administration, and the apparent clearance rate (CL/F) was 15.3L kg-1. H-1; the activity of CYP3A in broilers was inhibited by ketoconazole in the body of broilers. The area under the curve of drug plasma increased to 1.12 G. ML-1. H, and the apparent scavenging rate was 14.8 L-kg-1. H-1. There was no significant change in the apparent clearance rate. The area under the drug time curve was 1.29 mu g. ML-1. H in broiler chickens. The results showed that CYP3A was a substitute for the CYP3A to AA broilers. The effect of P-gp was not obvious, but the effect was significant.

【學位授予單位】：南京農業(yè)大學
【學位級別】：碩士
【學位授予年份】：2015
【分類號】：S859.796

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