芒果苷大鼠肠吸收特性研究

目的研究芒果苷在大鼠肠道的吸收动力学特征。方法采用大鼠在体肠循环实验,用超高效液相色谱法和紫外分光光度法分别测定芒果苷和酚红的浓度,考察药物浓度、pH值和不同肠段对芒果苷吸收的影响,并与知母水煎液比较芒果苷在大鼠肠道吸收的差异。结果芒果苷浓度为2.0,5.0,10.0,20.0μg.mL-1时,吸收速率常数(ka)分别是0.0541,0.0467,0.0491,0.0220 h-1,吸收百分率(Fa)分别是14.05%,13.14%,12.43%和5.82%;随肠液pH升高,ka和Fa依次增加;芒果苷在肠段内吸收存在差异,各肠段的吸收速率常数按结肠、十二指肠、回肠和空肠依次下降;知母水煎液组中,肠循环液中芒果苷含量的上升和新芒果苷含量的下降呈同步变化。结论芒果苷在大鼠小肠段的吸收存在高浓度饱和现象,并且受到药物浓度、肠循环液pH值、肠段等因素的影响。     

连翘苷在大鼠小肠的吸收特性研究

目的 研究连翘苷在大鼠小肠的吸收特性。方法 采用外翻肠囊法建立连翘苷大鼠小肠吸收模型,HPLC测定连翘苷的含量,分别进行大鼠小肠的十二指肠、空肠、回肠3个肠段、不同浓度吸收特性研究,以及P-糖蛋白(P-gp)抑制剂盐酸维拉帕米和吸收促进剂吐温-80对连翘苷吸收的影响研究。结果 连翘苷浓度为10,20,40 μg·mL^-1 3个浓度时,吸收速度常数ka无显著性差异(P>0.05);在不同肠段中的吸收,通过量由多到少依次为回肠>空肠>十二指肠;加入盐酸维拉帕米和吐温-80的小组与正常组相比,吸收速度常数ka无显著性差异(P>0.05)。结论 在试验剂量范围内,连翘苷的吸收呈一级动力学过程,吸收机制主要为被动扩散;连翘苷不是P-糖蛋白的底物。     

在体肠灌流模型研究灵仙新苷的大鼠肠吸收特性

目的:研究灵仙新苷在大鼠肠段的吸收特征。方法:以酚红为标示物,采用在体单向肠灌流模型,LC-MS/MS测定灵仙新苷在体肠灌流的浓度变化,研究灵仙新苷的吸收部位和吸收动力学特征。结果:灵仙新苷在大鼠小肠各肠段的吸收速率常数(Ka)、有效渗透系数(Peff)是十二指肠>空肠≈回肠,且十二指肠的Ka和Peff值与其他肠段存在显著性差异(P<0.05);灌流液中同一肠段不同浓度灵仙新苷的Ka和Peff均无统计学显著差异;盐酸维拉帕米和环孢素A均显著性降低对灵仙新苷的吸收(P<0.05)。结论:灵仙新苷在小肠有不同程度的吸收,其中在十二指肠吸收最好,药物浓度对灵仙新苷的Peff和Ka值无影响,其吸收机制为被动扩散,灵仙新苷可能不是P-糖蛋白底物。     

溴吡斯的明在大鼠离体肠的吸收动力学

目的观察溴吡斯的明在各肠段的吸收动力学特征。方法采用大鼠外翻肠囊模型,反相离子对色谱法测定不同浓度(25、50、100 mg.L-1)的溴吡斯的明在各肠段的吸收量,计算吸收速率常数(Ka)和表观渗透系数(Papp),并考察P-糖蛋白抑制剂(环孢素和维拉帕米)对药物吸收的影响。结果在25、50、100 mg.L-1溴吡斯的明条件下,Ka按十二指肠、空肠、回肠、结肠依次减小,不同浓度溴吡斯的明对同一肠段的Ka无显著影响(P>0.05),十二指肠、空肠、回肠间的Ka无显著差异(P>0.05),在50、100 mg.L-1溴吡斯的明条件下,结肠的Ka与十二指肠、空肠、回肠比较有显著差异(P<0.05,P<0.01)。随着溴吡斯的明浓度增加,各肠段Papp显著降低,不同肠段间的Papp有显著差异(P<0.05,P<0.01)。P-糖蛋白抑制剂对溴吡斯的明吸收无影响(P>0.05)。结论溴吡斯的明在十二指肠有较好吸收,在空肠和回肠有一定吸收,在结肠中吸收较少。     

补肾温肺微乳中黄芪甲苷的大鼠在体肠吸收特征研究

目的:研究补肾温肺微乳中黄芪甲苷的大鼠不同肠段的吸收特性,并考察P-糖蛋白(P-gp)对其肠吸收的影响。方法:采用大鼠在体单向肠灌流实验,采用HPLC法测定黄芪甲苷的含量,分别研究肠段不同吸收部位、黄芪甲苷浓度、P-糖蛋白抑制剂盐酸维拉帕米对黄芪甲苷单体及其在补肾温肺微乳中吸收的影响。结果:黄芪甲苷单体在各肠段的吸收速率常数(K_a)和表观吸收系数(P_app)有显著性差异(P<0.05);流速在0.10~0.40 ml·min^-1内和质量浓度在0.1~1.0 mg·ml^-1范围内,十二指肠吸收速率常数和表观吸收系数无显著性差异;补肾温肺微乳中黄芪甲苷的肠灌流试验结果与黄芪甲苷单体相比略小,但无显著性差异;P-糖蛋白抑制剂对黄芪甲苷的肠吸收影响很小。结论:黄芪甲苷和补肾温肺微乳中黄芪甲苷在大鼠不同肠段的吸收具有相似的吸收特性;其在大鼠肠内的吸收不受P-糖蛋白影响。因此,推测黄芪甲苷不是P-gp的底物。     

头孢唑肟致尿毒症透析患者中枢神经系统不良反应1例

目的研究连翘苷在大鼠小肠的吸收特性。方法采用外翻肠囊法建立连翘苷大鼠小肠吸收模型,HPLC测定连翘苷的含量,分别进行大鼠小肠的十二指肠、空肠、回肠3个肠段、不同浓度吸收特性研究,以及P-糖蛋白（P-gp）抑制剂盐酸维拉帕米和吸收促进剂吐温-80对连翘苷吸收的影响研究。结果连翘苷浓度为10,20,40μg.mL-1 3个浓度时,吸收速度常数ka无显著性差异（P〉0.05）;在不同肠段中的吸收,通过量由多到少依次为回肠〉空肠〉十二指肠;加入盐酸维拉帕米和吐温-80的小组与正常组相比,吸收速度常数ka无显著性差异（P〉0.05）。结论在试验剂量范围内,连翘苷的吸收呈一级动力学过程,吸收机制主要为被动扩散;连翘苷不是P-糖蛋白的底物。     

盐酸麻黄碱的大鼠肠吸收研究

目的：研究盐酸麻黄碱的肠吸收机制。方法：利用大鼠在体单向肠灌流模型,采用HPLC法测定灌流液中盐酸麻黄碱含量,分别考察灌流速度、盐酸麻黄碱质量浓度、不同肠段以及P-糖蛋白抑制剂对盐酸麻黄碱肠吸收的影响。结果：灌流速度对盐酸麻黄碱吸收速率常数（Ka）和表观吸收系数（Papp）有极显著影响（P〈0.01）;灌流液中盐酸麻黄碱质量浓度对Ka和Papp无显著影响（P〉0.05）;盐酸麻黄碱在小肠各肠段（十二指肠、空肠和回肠）的Ka和Papp无显著性差异（P〉0.05）,但其Ka值显著大于在结肠处的值（P〈0.05）,而各肠段的Papp无显著性差异（P〉0.05）,P-糖蛋白抑制剂对盐酸麻黄碱在各肠段的Ka和Papp无显著影响（P〉0.05）。结论：盐酸麻黄碱在大鼠肠道内的吸收机制为被动扩散,不存在饱和吸收;其在全肠道吸收较好,吸收窗主要在小肠,且小肠内无明显的特定吸收部位;盐酸麻黄碱可能不是P-糖蛋白的底物。     

基于原位单向肠灌流模型研究没食子酸的肠吸收特性

目的考察没食子酸的肠道吸收特性,为提高鞣质类成分生物利用度提供理论依据。方法采用大鼠在体肠单向灌流模型、建立HPLC测定没食子酸的方法,并计算没食子酸在各肠段的吸收速率常数(Ka)及有效表观渗透率系数(Peff);分别研究吸收部位、药物浓度、时间、pH值、P-糖蛋白(P-gp)和多药耐药相关蛋白-2(MRP2)抑制剂对没食子酸吸收的影响。结果没食子酸在不同肠段的Ka顺序为空肠>十二指肠>回肠≈结肠;随着药物浓度的升高,没食子酸的吸收差异无显著性;酸性环境(pH 5.5)有利于没食子酸的吸收;加入P-gp和MRP2抑制剂后,没食子酸的吸收与不加P-gp和MRP2抑制剂比较差异有显著性(P<0.05)。结论没食子酸在大鼠肠道内有较好的吸收,在空肠中吸收最好。初步判断其吸收机制为被动扩散。没食子酸的吸收受P-gp和MRP2的外排影响,可能为P-gp和MRP2底物。     

芒果苷大鼠在体肠道吸收机制研究

目的:研究芒果苷大鼠在体肠道吸收机制。方法:采用大鼠在体肠段灌流模型,建立高效液相色谱/紫外分光光度法测定肠循环液中芒果苷的浓度,研究不同芒果苷浓度、胆汁及吸收部位对芒果苷吸收参数的影响。结果:芒果苷在5.0~25.0μg.mL-1浓度范围内对小肠吸收速率常数(Ka)无影响;在12.5μg.mL-1浓度下对结扎胆管大鼠的小肠Ka有影响;各肠段的Ka回肠>空肠>结肠>十二指肠,分别为0.164、0.132、0.125、0.107h-1。结论:芒果苷的吸收符合一级动力学特征,吸收机制为被动扩散;芒果苷在各肠段均有较好的吸收,胆汁使芒果苷在小肠的透过系数增大。     

西替利嗪肠吸收机制研究

目的:考察西替利嗪在小肠的吸收特征.方法:采用离体肠外翻法,以HPLC法测定不同浓度西替利嗪在大鼠各肠段的吸收量,并分别计算吸收速率常数(Ka)和表观渗透系数.考察P-糖蛋白(P-gp)抑制剂地高辛和多药耐药相关蛋白-2(Mrp-2)抑制剂丙磺舒对西替利嗪肠吸收的影响.结果:西替利嗪在各肠段均有较好的吸收,Ka和表观渗透系数按空肠、十二指肠、结肠和回肠依次下降.各肠段累积吸收量与浓度呈非线性关系,高浓度时吸收加快.P-gp抑制剂地高辛使西替利嗪的吸收明显增加,而Mrp-2抑制剂丙磺舒对西替利嗪的肠吸收没有明显影响.结论:西替利嗪的转运受P-gp介导,临床应用中需注意P-gp及其底物对西替利嗪体内过程的影响.     

在体单向灌流法研究阿哌沙班肾衰大鼠肠吸收特性

目的 研究阿哌沙班在肾衰大鼠体内的肠吸收特性,并考察P糖蛋白(P-glycoprotein,P-gp)抑制剂对阿哌沙班吸收行为的影响。方法 选择肾衰大鼠在体单向灌流法进行肠吸收实验,建立大鼠阿哌沙班肠灌流液HPLC分析方法,以考察大鼠在体肠吸收影响因素。结果 阿哌沙班在各肠段的吸收速率常数（K_a）存在显著性差异（P<0.05）,但表观吸收系数（P_app）未见明显差异（P>0.05）;大鼠回肠段的K_a和P_app值随药物浓度的增加而降低;加入 P-gp抑制剂盐酸维拉帕米（0.1 mmol/L）后,阿哌沙班在空肠和回肠段的K_a和P_app值均明显增加。结论 阿哌沙班在各肠段均有吸收;P-gp抑制剂对阿哌沙班在空肠和回肠段的吸收均有明显的促进作用,表明阿哌沙班为P-gp底物,推测其吸收机制为主动转运。     

Different absorption behaviors among steroid hormones due to possible interaction with P-glycoprotein in the rat small intestine.

The intestinal absorption of ten steroid hormones was evaluated in the rat small intestine, especially focusing on the interaction with intestinal P-glycoprotein (P-gp). Hydrocortisone, prednisolone, 6alpha-methylprednisolone, and dexamethasone (adrenocortical steroid hormones) all disappeared in a regional-dependent manner (duodenum>jejunum>ileum). The decreased rate of disappearance in the lower small intestine seemed to be due to the involvement of absorption barriers like P-gp. In contrast, all sex hormones including progesterone exhibited very high absorbability in the entire small intestine (duodenum=jejunum=ileum), possibly demonstrating the absence of restricted absorption by intestinal P-gp. Progesterone enhanced the rate of disappearance of vinblastine but did not affect 6alpha-methylprednisolone. In the presence of vinblastine and verapamil, on the other hand, the rate of disappearance of 6alpha-methylprednisolone increased significantly. It was demonstrated that there was a plural P-gp family, which had different substrate specificities, in the rat intestine and that steroid hormones interacted with them as substrates or inhibitors in a very complex manner.     

Effects of sodium deoxycholate and sodium caprate on the transport of epirubicin in human intestinal epithelial Caco-2 cell layers and everted gut sacs of rats

The effects of sodium deoxycholate (Deo-Na), a bile salt, and sodium caprate (Cap-Na), a fatty acid, on the transport of epirubicin were investigated in both the human colon adenocarcinoma (Caco-2) cell line and the everted gut sacs of the rat jejunum and ileum. The possible use of these two potent absorption enhancers as multidrug resistance (MDR) reversing agents also was examined. Epirubicin uptake experiments using a flow cytometer showed that Deo-Na and Cap-Na significantly increased the accumulation of epirubicin in Caco-2 cells. These two enhancers significantly increased apical to basolateral absorption of epirubicin across Caco-2 monolayers and mucosal to serosal absorption of epirubicin in the rat jejunum and ileum. Moreover, the addition of Deo-Na or Cap-Na significantly reduced the basolateral to apical efflux of epirubicin across Caco-2 monolayers. The co-presence of verapamil, one typical P-glycoprotein (P-gp) substrate, and Deo-Na or Cap-Na demonstrated further reduction of epirubicin efflux. The study suggests that inhibition of P-gp or other transporter proteins located in the intestines may be involved, at least partially, in the reduction of epirubicin efflux. In conclusion, the therapeutic efficacy of epirubicin may be improved by the use of such low toxicity excipients as absorption enhancers and MDR modulators in formulations.     

Enhancing effect of N-octyl-O-sulfate chitosan on etoposide absorption

P-glycoprotein (P-gp), expressed in the apical membranes of the epithelial cells of the intestine, can reduce the oral bioavailability of a wide range of drugs. Many surfactants/excipients have been demonstrated to potentially increase drug absorption by inhibiting P-gp. The purpose of the present study was to evaluate the effect of N-octyl-O-sulfate chitosan (NOSC) on the absorption of etoposide (VP16), a substrate of P-gp with low water solubility. The rat intestinal circulating perfusion in situ and Caco-2 cell uptake and monolayer membrane penetration in vitro were performed to investigate the enhancing ability of NOSC in comparison with some other P-gp inhibitors. The results indicated that various concentrations of NOSC all increased the intestinal absorption of VP16 in rat jejunum and ileum obviously and there was no significant difference in ileum between the enhancing effects of NOSC and other P-gp inhibitors. The VP16 uptake of Caco-2 cell was increased by NOSC solution with different concentrations. As the NOSC concentration was close to its critical micelle concentration (CMC), the cell uptake of VP16 reached to a maximum value. Both NOSC and verapamil (Ver) enhanced dramatically the transport of VP16 from apical side to basolateral side in Caco-2 cell monolayers. Moreover, they both decreased notably the transport of VP16 from basolateral side to apical side, but this effect of NOSC was weaker than that of Ver. However, transepithelial electrical resistance (TEER) of Caco-2 cell monolayers had no significant change during the study. These studies demonstrated that NOSC had the potential by inhibiting P-gp to improve the absorption of oral drugs which were P-gp substrates.     

N-［8-(2-羟苯基)氨基］辛酸钠对胰岛素溶液的胃肠道吸收促进作用及机理

目的研究一种合成的吸收促进剂N-［8-(2-羟苯基)氨基］辛酸钠(SNAC)对胰岛素(INS)溶液胃肠道给药的吸收促进作用及作用机制。方法小鼠和大鼠灌胃给药考察SNAC对INS溶液的吸收促进作用;采用大鼠不同肠段给药、能量抑制剂2,4-二硝基苯酚(DNP)和P-糖蛋白抑制剂维拉帕米(Ver)研究SNAC 的促吸收作用机理。结果SNAC可促进INS溶液在消化道的吸收,作用大小与SNAC的量成正比;SNAC的促吸收作用空肠>结肠>回肠,随DNP浓度增大而减小,随Ver浓度增大而增大。结论SNAC对INS的吸收促进作用呈剂量依赖,需要能量,受P-糖蛋白排放影响。     

Role of intestinal efflux transporters in the intestinal absorption of methotrexate in rats

The role of intestinal efflux transporters such as P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and multidrug resistance-associated proteins (MRPs) in intestinal absorption of methotrexate was examined in rats. In everted intestine, the mucosal efflux of methotrexate after application to serosal side was higher in jejunum than ileum, and the efflux in jejunum was suppressed by pantoprazole, a BCRP inhibitor, and probenecid, an MRP inhibitor, but not by verapamil, a P-gp inhibitor. The mucosal methotrexate efflux in ileum was suppressed by pantoprazole, but not by other inhibitors. On the other hand, the serosal efflux of methotrexate after application to mucosal side was greater in ileum than jejunum, and was suppressed by probenecid. In in-vivo rat studies, the intestinal absorption of methotrexate was significantly higher when methotrexate was administered to ileum than jejunum. Pantoprazole increased methotrexate absorption from jejunum and ileum. Probenecid increased the absorption of methotrexate from jejunum but decreased the absorption from ileum, as evaluated by peak plasma methotrexate levels. In conclusion, BCRP and MRPs are involved in the regional difference in absorption of methotrexate along the intestine, depending on their expression sites.     

在体单向肠灌流模型研究小檗碱及其在复方配伍环境中的大鼠肠吸收特性

本实验主要考察药物浓度、肠段、pH、P-糖蛋白 (P-glycoprotein, P-gp) 及Na⁺依赖型葡萄糖转运体 (Na⁺-dependent glucose transporter, SGLT1) 对小檗碱肠吸收的影响, 并探索复方配伍环境中小檗碱的肠吸收情况。实验以酚红为标示物, 采用大鼠在体单向肠灌流模型, 运用高效液相色谱法考察小檗碱单体 (36.70、46.17和92.33 μg·mL⁻¹)、黄连解毒汤模拟体系 (主要指标成分单体混合物: 小檗碱 + 黄芩苷 + 栀子苷, 其中小檗碱浓度为92.33 μg·mL⁻¹) 及黄连解毒汤全方 (小檗碱浓度为92.33 μg·mL⁻¹) 中小檗碱在大鼠各肠段的吸收变化情况。结果表明: 小檗碱在一定浓度范围内 (20～100 μg·mL⁻¹), 部分大鼠小肠吸收速率参数 (K_a) 无显著性差异, 提示药物的吸收机制可能为被动扩散, 其转运过程可能受SGLT1和P-gp的影响; 单体混合物和全方中小檗碱在各肠段的K_a和有效渗透系数 (P_eff) 值均有显著性增加 (P < 0.05)。说明小檗碱在整个肠段均有吸收, 具有广泛的吸收窗, 其中结肠段吸收较好; 配伍对小檗碱的大鼠肠吸收特性有一定影响, 较单体而言, 单体混合物和全方灌流时小檗碱在小肠中吸收更好。     

Improvement of intestinal absorption of P-glycoprotein substrate by D-tartaric acid

The purpose of the present experiment was to examine the effects of D-tartaric acid (TA) on intestinal drug absorption under both in situ and in vitro experimental conditions. In the in vitro diffusion chamber experiments, TA (10 mM) added to the mucosal side of rat colon significantly decreased rhodamine123 (Rho 123) transport from the serosal to mucosal side. Since TA has been shown to change the integrity of the epithelial tight junctions in rat colon at low pH conditions, resulting in improved paracellular drug transport, the effect of TA on membrane resistance was examined at pH 7.4 in the present study. It was found that membrane resistance, an indicator of paracellular integrity, did not change at pH 7.4. In the in situ loop method, TA (20 mM) increased the absorption of Rho123 in both ileum and colon but not in jejunum. TA (20 mM) also increased the absorption of daunorubicin in the ileum, but TA (20 mM) did not change the expression level of P-glycoprotein (P-gp). TA (20 mM) significantly inhibited excretion of i.v.-administered Rho123 and daunorubicin into the ileal lumen. In conclusion, for the first time we demonstrated that TA increases the intestinal absorption of P-gp substrates Rho123 and daunorubicin, possibly by modulating the P-gp function without changing the expression level of P-gp in the rat intestine.