Wang Zhi-Ying, Zhang Qiang
Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100083, China.
Yao Xue Xue Bao. 2003 Dec;38(12):957-61.
To study the relationship between cellular membrane fluidity and relative bioavailability (Fr) of protein and peptide drugs combined with absorption enhancers after pulmonary administration in rats.
A series of model drug salmon calcitonin (sCT) solutions with 6 absorption enhancers (Brij78, sodium cholate, sodium caprylate, 2-hydroxypropyl-beta-cyclodextrin, lecithin and chitosan) were prepared and then delivered to rats by pulmonary route. Serum drug concentration was determined by radioimmunoassay method. Using the techniques of electron spin resonance and fluorescence polarography, the effects of enhancers on pulmonary cellular membrane fluidity were investigated.
Fr values of sCT solution with some absorption enhancers (Brij78, sodium cholate, sodium caprylate, lecithin and chitosan) were significantly higher than those without enhancers. Brij78, lecithin and sodium caprylate, not only increased membrane lipid fluidity but also loosed the constitution of membrane protein. The effect of sodium cholate on membrane protein was low. Lipid fluidity was reduced and protein constitution was changed markedly, after pulmonary cellular membrane was treated by 0.5% chitosan solution. This result showed that the absorption enhancing of chitosan mainly came from its effects on membrane protein. Corresponded with lower Fr after pulmonary administration, 2-hydroxypropyl-beta-cyclodextrin (0.5% and 3%) had not significant effects on both lipid fluidity and protein constitution.
The effects of enhancers on pulmonary absorption of peptide drugs in vivo might be investigated on the grounds of determination of cellular membrane fluidity in vitro.
研究大鼠肺部给药后，细胞膜流动性与蛋白质和肽类药物联合吸收促进剂的相对生物利用度（Fr）之间的关系。
制备一系列含6种吸收促进剂（Brij78、胆酸钠、辛酸钠、2-羟丙基-β-环糊精、卵磷脂和壳聚糖）的模型药物鲑鱼降钙素（sCT）溶液，然后经肺部途径给予大鼠。采用放射免疫分析法测定血清药物浓度。运用电子自旋共振和荧光偏振技术，研究促进剂对肺细胞膜流动性的影响。
含某些吸收促进剂（Brij78、胆酸钠、辛酸钠、卵磷脂和壳聚糖）的sCT溶液的Fr值显著高于不含促进剂的溶液。Brij78、卵磷脂和辛酸钠不仅增加了膜脂质流动性，还使膜蛋白结构松散。胆酸钠对膜蛋白的作用较小。用0.5%壳聚糖溶液处理肺细胞膜后，脂质流动性降低，蛋白结构明显改变。这一结果表明壳聚糖的吸收促进作用主要源于其对膜蛋白的影响。与肺部给药后较低的Fr值相对应，2-羟丙基-β-环糊精（0.5%和3%）对脂质流动性和蛋白结构均无显著影响。
可基于体外细胞膜流动性的测定来研究促进剂对体内肽类药物肺部吸收的影响。
