影响酒石酸泰万菌素口服生物利用度因素的初步研究

发布时间：2018-04-26 09:28

本文选题：酒石酸泰万菌素 + 口服生物利用度　；参考：《南京农业大学》2015年硕士论文

【摘要】：为探讨影响酒石酸泰万菌素口服生物利用度的因素,本研究采用鸡肝原代细胞模型、Caco-2细胞模型和小肠灌流模型,体外研究酒石酸泰万菌素代谢消除和吸收转运。并通过抑制CYP3A和P-gp,考察其对酒石酸泰万菌素在AA肉鸡体内的药动学影响。具体分为以下几个部分:1酒石酸泰万菌素生物利用度的研究为了研究酒石酸泰万菌素的口服生物利用度,建立了血浆、培养基和缓冲液中酒石酸泰万菌素的处理及高效液相(HPLC)色谱分析方法。1日龄的AA肉鸡饲喂至28日龄后,挑选20只健康雄性肉鸡,分为口服和静脉给药两组,每组10只,分别灌服和静注10mg·kg-1.b.w的酒石酸泰万菌素溶液。给药后24h内,翅下静脉采血,用HPLC法测定酒石酸泰万菌素血药浓度,用3P97药动学软件分析药-时数据。结果显示,建立的HPLC方法符合定量检测要求。肉鸡单剂量口服和静注酒石酸泰万菌素的药动学过程符合二室开放模型。口服后血浆中泰万菌素的药时曲线下面积(AUC)为0.82μg·mL-1·h,达峰时间(Tmax)0.72h;静注后血浆中泰万菌素的药时曲线下面积(AUC)为6.47μg·mL-1·h。结果表明,酒石酸泰万菌素口服后,吸收迅速,但口服生物利用度(F)低,仅有12.67%。2影响酒石酸泰万菌素口服生物利用度部位的定量研究1日龄的AA肉鸡饲喂至42日龄后,挑选40只健康雄性肉鸡,随机分为口服给药组、十二指肠给药组、门静脉给药组和静脉给药组,每组10只。肉鸡麻醉后,以10 mg·kg-1剂量按以上给药方式给予酒石酸泰万菌素溶液。给药后24 h内,翅下静脉采血,用HPLC法测定酒石酸泰万菌素血药浓度,用3P97药动学软件分析药-时数据。结果显示,不同途径给药后,酒石酸泰万菌素的药动学过程符合二室开放动力学模型。静脉给药组的曲线下面积(AUC)显著高于门静脉给药组;静脉和门静脉给药组都显著高于口服给药组。结果表明,酒石酸泰万菌素的口服生物利用度主要受肠道和肝脏影响。肠道影响最大,达87.2%,其次为肝脏,达16.2%。3酒石酸泰万菌素代谢消除和吸收转运的体外研究利用肝原代细胞体外代谢模型、Caco-2单层细胞体外转运模型和肠道灌流模型,分别研究酒石酸泰万菌素的体外代谢消除和体外吸收转运。利用肝原代细胞体外代谢模型,以不同浓度的酒石酸泰万菌素考察代谢消除,并抑制CYP1A和CYP3A活性,考察它们对酒石酸泰万菌素代谢的影响;运用Caco-2单层细胞体外转运模型研究酒石酸泰万菌素吸收特点,同时考察p-gp对其转运的影响;运用肠道灌流模型,添加EGTA和抑制P-gp,分别对十二指肠、空肠和回肠进行单向灌流,考察酒石酸泰万菌素吸收的主要肠段和P-gp对酒石酸泰万菌素转运的影响。结果显示,酒石酸泰万菌素在肝细胞中存在着代谢消除,而且有时间依赖性和浓度依赖性,符合酶促动力学特征。CYP3A被抑制后,酒石酸泰万菌素代谢消除显著减慢。Caco-2细胞中,转运呈现细胞旁转运和跨细胞转运并存;EGTA的存在会使转运系数增加;存在P-gp介导的外排现象。而在小肠灌流过程中,十二指肠吸收迅速,是主要吸收肠段,吸收方式以跨细胞转运为主;EGTA的存在难以提高吸收效率,维拉帕米的存在可以显著降低P-gp介导的外排;各肠段的转运系数说明在十二指肠吸收良好,空肠和回肠的吸收较差。结果表明,CYP3A参与了酒石酸泰万菌素的代谢消除,由它引起的首过效应会使酒石酸泰万菌素的口服生物利用度降低,另外,肠道的吸收不良、P-gp介导的外排及在肠系膜中的代谢也是酒石酸泰万菌素口服生物利用度低的原因。4 CYP3A以及P-gp对酒石酸泰万菌素在AA肉鸡体内的药动学影响1日龄的AA肉鸡饲喂至42日龄后,挑选60只健康雄性肉鸡,随机分为酮康唑处理组、维拉帕米处理组以及对照组,每组20只。酮康唑处理组按照60 mg·kg-1.b.w的剂量给动物灌服酮康唑,1天1次,第3天灌药0.5 h后,按10mg·kg-1.b.w灌服和静注酒石酸泰万菌素溶液;其它两组分别连续灌服9 mg·kg-1.b.w的维拉帕米和相同体积的生理盐水,第3天灌药0.5 h后,按10 mg·kg-1.b.w灌服和静注酒石酸泰万菌素溶液。给药后24 h内,翅下静脉采血,用HPLC法测定酒石酸泰万菌素血药浓度,用3P97药动学软件分析药-时数据。结果表明,肉鸡以单剂量口服和静注酒石酸泰万菌素的药动学过程符合二室开放动力学模型。口服给药后对照组的药-时曲线下面积(AUC)为0 96μg·mL-1·h,表观清除率(CL/F)为 15.3L·kg-1·h-1;肉鸡体内 CYP3A 活性被酮康唑特异性抑制后,血浆中泰万菌素的药时曲线下面积上升到1.12 μg·mL-1·h,表观清除率为14.8 L-kg-1·h-1,均没有显著变化;肉鸡体内P-gp被维拉帕米特异性抑制后,药-时曲线下面积为1.29μg·mL-1·h,显著升高。结果显示,CYP3A对酒石酸泰万菌素在AA肉鸡体内的代谢消除影响不明显,而P-gp影响显著。
[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.

【学位授予单位】：南京农业大学
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：S859.796

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