摘要
目的研究三七总皂苷(PNS)的口服吸收机制。方法采用Caco-2细胞和动物等模型研究PNS中人参皂苷Rb1(Rb1)和人参皂苷Rg1(Rg1)的胃肠道内稳定性、肠道黏膜吸收机制及吸收过程中胃、肠及肝对药物的影响。结果Rb1和Rg1在胃液酸性环境下易被破坏,而在近中性环境内基本保持稳定。Rb1和Rg1在大肠内容物中易降解,尤以Rb1降解较为明显;二者在小肠内容物中则相对稳定。Rb1和Rg1在Caco-2细胞层的摄取受温度的影响,而pH的变化及环孢菌素A的加入对二者摄取均无显著性影响。在实验考察的浓度范围内,细胞内Rb1(或Rg1)的摄取量随Rb1(或Rg1)的浓度的增加而呈线性增加,Rb1(或Rg1)单体与总皂苷中的Rb1(或Rg1)在Caco-2细胞模型中的吸收特性无明显差异。而Rg1的细胞摄取量[(1·07±0·16)μg·mg-1(protein)](C0=1mg·mL-1)相对Rb1[(0·77±0·03)μg·mg-1(protein)](C0=1mg·mL-1)较高。Caco-2细胞转运实验表明,Rb1和Rg1单体的转运透过系数(Papp)分别为(5·9±1·0)×10-8cm·s-1和(2·59±0·17)×10-7cm·s-1(C0=1mg·mL-1),二者转运都不受环孢菌素A影响。PNS溶液灌胃、十二指肠及门静脉给药后测得Rb1大鼠绝对生物利用度分别为0·71%,2·75%和65·77%;Rg1分别为3·29%,6·60%和50·56%。结论三七总皂苷(包括Rb1和Rg1)的肠道吸收机制为单纯被动扩散,吸收过程不受细胞膜内P-gp和MRP外排载体的调控,PNS中其他成分对Rb1或Rg1的吸收特性无明显影响。胃液的酸性环境、大肠菌丛产生的酶及肝脏的首过作用均对其口服吸收产生影响,而肠道黏膜的透过性低是其口服吸收差的主要影响因素。
Aim To study the mechanism of absorption after oral administration of panaxnotoginseng saponins （PNS）. Methods Caco-2 cells and rat models were applied to evaluate the degradation of both ginsenoside Rb1 （Rb1） and ginsenoside Rg1（ Rg1 ） in PNS in gastrointestinal lumen, and the transport mechanism of PNS across the intestinal mucosa, and the barrier function of stomach, intestine and liver involved in absorption process. Results Rb1 and Rg1 proved to be readily eliminated in stomach, but stable in relatively neutral circumstance. Both Rb1 and Rg1 in PNS, especially for Rb1, degraded significantly in the contents of large intestine. However, both of them kept mainly intact in the contents of small intestine. Uptake of both Rb1 and Rg1 by Caco-2 cell monolayer was inhibited at low temperature, but not by cyclosporine A, and the change in the apical pH showed no pronounced effect. Uptake and transport were non-saturable and increased linearly with increasing of concentrations of Rb1 and Rg1 over the range of concentration tested, which indicated a passive transport. There was no significant difference of absorption characteristic between monomer （ Rb1 and Rg1 ） and mixture （PNS）. Uptake amount of Rg1 [（1.07＋0.16） μg·mg^-1（protein）] （C0=1 mg· mL^-1） in Caco-2 cells was alittle higher than that of Rb1 [ （0. 77 ＋0. 03 ） μg·mg^-1（protein） ] （ C0 = 1 mg· mL^-1 ）. Meanwhile, apparent permeability coefficient of （ 5. 9 ＋1.0） ×10^-8cm·s^-1（C0 =1 mg · mL^-1） for Rb1 and （2.59 ＋0.17） ×10^-7 cm· s^-1 （Co = 1 mg · mL^-l） for Rg1 from apical compartment to basolateral compartment predicted an incompletely absorption. Transports of both Rb1 and Rg1 were not influenced by cyclosporine A. The investigation on the pharmacokinetic behavior of Rb1 and Rg1 after different routes of administration to rats showed that the absolute bioavailability after peroral （po）, intraduodenal （id）, and portal venous （pv） administration is 0. 71%, 2. 75% and 65.77% respectively for Rb1 , and 3.29%, 6.60% and 50. 56% respectively for Rg1. Conclusion Transport across Caco-2 cell monolayer for PNS （ include Rb1 and Rg1 ） is a simple passive diffusion process. No efflux transporters in Caco-2 cells and other components in PNS showed effects on it. The elimination in stomach, large intestine and liver contributed to the low bioavailability of PNS, but the low membrane permeability might be a more important factor dominating the extent of absorption.
出处
《药学学报》
CAS
CSCD
北大核心
2006年第6期498-505,共8页
Acta Pharmaceutica Sinica
作者简介
通讯作者Tel／Fax：86—21—54237432．E—mail：xlfang@shmu．edu．cn
