AIM： To characterize the intestinal transport and mechanism of metformin in rats and to investigate whether or not metformin is a substrate for P-glycoprotein （P-gp）. METHODS： The effective intestinal permeability...AIM： To characterize the intestinal transport and mechanism of metformin in rats and to investigate whether or not metformin is a substrate for P-glycoprotein （P-gp）. METHODS： The effective intestinal permeability of metformin was investigated using single-pass intestinal perfusion （SPIP） technique in male Waster rats. SPIP was performed in three isolated intestinal segments （duodenum, jejunum and ileum） at the same concentration of metformin （50 μg/mL） to test if the intestinal transport of metformin exhibited site- dependent changes, and in a same isolated intestinal segment （duodenal segment） at three different concentrations of metformin （10, 50, 200 μg/mL） to test if the intestinal transport of metformin exhibited concentration-dependent changes. Besides, P-gp inhibitor verapamil （400 μg/mL） was co-perfused with metformin （50 μg/mL） in the duodenum segment to find out if the intestinal absorption of metformin was affected by P-gp exiting along the gastrointestinal track. Stability studies were conducted to ensure that the loss of metformin could be attributed to intestinal absorption. RESULTS： The effective permeability values （Peff） of metformin in the jejunum and ileum at 50μg/mL were significantly lower than those in the duodenum at the same concentration. Besides, Peff values in the duodenum at high concentration （200 μg/mL） were found to be significantly lower than those at low and medium concentrations （10 and 50 μg/mL）. Moreover the coperfusion with verapamil did not increase the Peff value of metformin at 50 μg/mL in the duodenum.CONCLUSION： Metformin could be absorbed from the whole intestine, with the main absorption site at duodenum. This concentration-dependent permeability behavior in the duodenum indicates that metformin is transported by both passive and active carrier-mediated saturable mechanism. The Peff value can not be increased by co-perfusion with verapamil, indicating that absorption of metformin is not efficiently transported by P-gp in the gut wall. Furthermore metformin is neither a substrate nor an inducer of P-gp. Based on the Peff values obtained in the present study and using established relationships, the human fraction dose absorbed for metformin is estimated to be 74%-90% along human intestine.展开更多
Garcinia Glycosides is a candidate drug obtained by structural modification of Gambogic Acid (GA), which was acquired through High Throughput Screening(HTS). As Garcinia Glycosides is an effective but insoluble anti-t...Garcinia Glycosides is a candidate drug obtained by structural modification of Gambogic Acid (GA), which was acquired through High Throughput Screening(HTS). As Garcinia Glycosides is an effective but insoluble anti-tumor drug, the aim of this study was to obtain a solid dispersion form Garcinia Glycosides by using solvent-melt method so that improve the solubility and dissolution rate. The solid dispersion was characterized by High Performance Liquid Chromatography (HPLC), infrared spectroscopy and evaluated the intestinal absorption of the drug by rat in situ single pass intestinal perfusion. The results showed the increase of solubility, dissolution velocity and absorption compared to other forms. This indicated that solid dispersion could greatly improve the relative bioavailability of Garcinia Glycosides in vivo.展开更多
AIM: To investigate the absorption characteristics of the total alkaloids from Mahoniae Caulis(TAMC) through the administration of monterpene absorption enhancers or protein inhibitors. METHOD: The absorption behavior...AIM: To investigate the absorption characteristics of the total alkaloids from Mahoniae Caulis(TAMC) through the administration of monterpene absorption enhancers or protein inhibitors. METHOD: The absorption behavior was investigated in an in situ single-pass intestinal perfusion(SPIP) assay in rats. RESULTS: The intestinal absorption of TAMC was much more than that of a single compound or a mixture of compounds(jatrorrhizine, palmatine, and berberine). Promotion of absorption by the bicyclic monoterpenoids(borneol or camphor) was higher than by the monocyclic monoterpenes(menthol or menthone), and promotion by compounds with a hydroxyl group(borneol or menthol) was higher than those with a carbonyl group(camphor or menthone). The apparent permeability coefficient(Papp) of TAMC was increased to 1.8-fold by verapamil, while it was reduced to one half by thiamine. The absorption rate constant(Ka) and Papp of TAMC were unchanged by probenecid and pantoprazole. CONCLUSION: The intestinal absorption characteristics of TAMC might be passive transport, and the intestinum tenue was the best absorptive site. In addition, TAMC might be likely a substrate of P-glycoprotein(P-gp) and organic cation transporters(OCT), rather than multidrug resistance protein(MRP) and breast cancer resistance protein(BCRP). Compared with a single compound and a mixture of compounds, TAMC was able to be absorbed in the blood circulation effectively.展开更多
目的考察微乳液递送吴茱萸碱(evodiamine loaded microemulsion,EDM)体外释放特征及大鼠的在体吸收情况。方法制备EDM,用透析法研究其在p H 1.2盐酸溶液和p H6.8磷酸缓冲溶液中的体外释放特征,计算其累积释放率。再用大鼠在体单向肠循...目的考察微乳液递送吴茱萸碱(evodiamine loaded microemulsion,EDM)体外释放特征及大鼠的在体吸收情况。方法制备EDM,用透析法研究其在p H 1.2盐酸溶液和p H6.8磷酸缓冲溶液中的体外释放特征,计算其累积释放率。再用大鼠在体单向肠循环法研究其在十二指肠、空肠、回肠和结肠的吸收情况,以及在胃的吸收情况,计算其在各部位的吸收速率常数(absorption rate constant,K_a)与有效渗透率(effective permeability,P_(eff))。本实验用HPLC法测定吴茱萸碱(evodiamine,ED)的浓度。结果EDM和ED在p H 1.2盐酸溶液中的累积释放率分别为(64.76±0.73)%、(13.98±0.49)%,EDM的累积释放率为ED的4.63倍;在p H 6.8磷酸缓冲液中的累积释放率分别为(91.72±0.51)%、(18.34±0.20)%,EDM的累积释放率为ED的5.01倍。EDM在胃肠的K_a为ED的3倍以上,P_(eff)为ED的2倍以上。结论微乳液能使ED的体外释放以及大鼠胃肠吸收均得以改善。展开更多
基金Supported by the National "863" Program of China, No.2003AA2Z347Dthe National "973" Program of China, No.2004CB518902
文摘AIM： To characterize the intestinal transport and mechanism of metformin in rats and to investigate whether or not metformin is a substrate for P-glycoprotein （P-gp）. METHODS： The effective intestinal permeability of metformin was investigated using single-pass intestinal perfusion （SPIP） technique in male Waster rats. SPIP was performed in three isolated intestinal segments （duodenum, jejunum and ileum） at the same concentration of metformin （50 μg/mL） to test if the intestinal transport of metformin exhibited site- dependent changes, and in a same isolated intestinal segment （duodenal segment） at three different concentrations of metformin （10, 50, 200 μg/mL） to test if the intestinal transport of metformin exhibited concentration-dependent changes. Besides, P-gp inhibitor verapamil （400 μg/mL） was co-perfused with metformin （50 μg/mL） in the duodenum segment to find out if the intestinal absorption of metformin was affected by P-gp exiting along the gastrointestinal track. Stability studies were conducted to ensure that the loss of metformin could be attributed to intestinal absorption. RESULTS： The effective permeability values （Peff） of metformin in the jejunum and ileum at 50μg/mL were significantly lower than those in the duodenum at the same concentration. Besides, Peff values in the duodenum at high concentration （200 μg/mL） were found to be significantly lower than those at low and medium concentrations （10 and 50 μg/mL）. Moreover the coperfusion with verapamil did not increase the Peff value of metformin at 50 μg/mL in the duodenum.CONCLUSION： Metformin could be absorbed from the whole intestine, with the main absorption site at duodenum. This concentration-dependent permeability behavior in the duodenum indicates that metformin is transported by both passive and active carrier-mediated saturable mechanism. The Peff value can not be increased by co-perfusion with verapamil, indicating that absorption of metformin is not efficiently transported by P-gp in the gut wall. Furthermore metformin is neither a substrate nor an inducer of P-gp. Based on the Peff values obtained in the present study and using established relationships, the human fraction dose absorbed for metformin is estimated to be 74%-90% along human intestine.
文摘Garcinia Glycosides is a candidate drug obtained by structural modification of Gambogic Acid (GA), which was acquired through High Throughput Screening(HTS). As Garcinia Glycosides is an effective but insoluble anti-tumor drug, the aim of this study was to obtain a solid dispersion form Garcinia Glycosides by using solvent-melt method so that improve the solubility and dissolution rate. The solid dispersion was characterized by High Performance Liquid Chromatography (HPLC), infrared spectroscopy and evaluated the intestinal absorption of the drug by rat in situ single pass intestinal perfusion. The results showed the increase of solubility, dissolution velocity and absorption compared to other forms. This indicated that solid dispersion could greatly improve the relative bioavailability of Garcinia Glycosides in vivo.
基金supported by China Pharmaceutical University Training Programs of Innovation for Undergraduates(No.02640390)
文摘AIM: To investigate the absorption characteristics of the total alkaloids from Mahoniae Caulis(TAMC) through the administration of monterpene absorption enhancers or protein inhibitors. METHOD: The absorption behavior was investigated in an in situ single-pass intestinal perfusion(SPIP) assay in rats. RESULTS: The intestinal absorption of TAMC was much more than that of a single compound or a mixture of compounds(jatrorrhizine, palmatine, and berberine). Promotion of absorption by the bicyclic monoterpenoids(borneol or camphor) was higher than by the monocyclic monoterpenes(menthol or menthone), and promotion by compounds with a hydroxyl group(borneol or menthol) was higher than those with a carbonyl group(camphor or menthone). The apparent permeability coefficient(Papp) of TAMC was increased to 1.8-fold by verapamil, while it was reduced to one half by thiamine. The absorption rate constant(Ka) and Papp of TAMC were unchanged by probenecid and pantoprazole. CONCLUSION: The intestinal absorption characteristics of TAMC might be passive transport, and the intestinum tenue was the best absorptive site. In addition, TAMC might be likely a substrate of P-glycoprotein(P-gp) and organic cation transporters(OCT), rather than multidrug resistance protein(MRP) and breast cancer resistance protein(BCRP). Compared with a single compound and a mixture of compounds, TAMC was able to be absorbed in the blood circulation effectively.
文摘目的考察微乳液递送吴茱萸碱(evodiamine loaded microemulsion,EDM)体外释放特征及大鼠的在体吸收情况。方法制备EDM,用透析法研究其在p H 1.2盐酸溶液和p H6.8磷酸缓冲溶液中的体外释放特征,计算其累积释放率。再用大鼠在体单向肠循环法研究其在十二指肠、空肠、回肠和结肠的吸收情况,以及在胃的吸收情况,计算其在各部位的吸收速率常数(absorption rate constant,K_a)与有效渗透率(effective permeability,P_(eff))。本实验用HPLC法测定吴茱萸碱(evodiamine,ED)的浓度。结果EDM和ED在p H 1.2盐酸溶液中的累积释放率分别为(64.76±0.73)%、(13.98±0.49)%,EDM的累积释放率为ED的4.63倍;在p H 6.8磷酸缓冲液中的累积释放率分别为(91.72±0.51)%、(18.34±0.20)%,EDM的累积释放率为ED的5.01倍。EDM在胃肠的K_a为ED的3倍以上,P_(eff)为ED的2倍以上。结论微乳液能使ED的体外释放以及大鼠胃肠吸收均得以改善。
