Twarog Caroline, McCartney Fiona, Harrison Sabine M, Illel Brigitte, Fattal Elias, Brayden David J
UCD School of Veterinary Medicine, Belfield, Dublin 4, Ireland; UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
UCD School of Agriculture and Food Science, Belfield, Dublin 4, Ireland.
Eur J Pharm Sci. 2021 Mar 1;158:105685. doi: 10.1016/j.ejps.2020.105685. Epub 2020 Dec 23.
SNAC and C are intestinal permeation enhancers (PEs) used in formulations of peptides for oral delivery in clinical trials. Our aims were to compare their: (i) mechanism of action in isolated rat intestinal mucosae mounted in Ussing chambers and in non-everted gut sacs, (ii) effects on mucosa integrity in those models and also in in situ intra-jejunal instillations and (iii) interactions with intestinal mucus. SNAC increased the apparent permeability coefficient (P) of the paracellular marker, FITC-dextran 4000 (FD4), across isolated rat gastric mucosae in concentration-dependent fashion, whereas C did not, while both reduced the transepithelial electrical resistance (TEER). In isolated jejunal and colonic mucosae, both agents increased the P of [C]-mannitol and FD4 whereas C but not SNAC reduced TEER. 20 mM SNAC was required to achieve the efficacy of 10 mM C in jejunal and colonic mucosae. In isolated non-everted jejunal and colonics sacs, FD4 flux increases were observed in the presence of both PEs. Histology of mucosae revealed that both PEs induced minor epithelial damage to the mucosa at concentrations that increased fluxes. Jejunal tissue withstood epithelial damage in the following order: intra jejunal in situ instillations > jejunal sacs > isolated jejunal mucosae. Both PEs modulated viscoelastic properties of porcine jejunal mucus without altering rheological properties. In conclusion, SNAC and C are reasonably efficacious PEs in rat intestinal tissue with common overall mechanistic features. Their potency and toxic potential are low, in agreement with clinical trial data.
SNAC和C是在临床试验中用于肽口服给药制剂的肠道渗透促进剂（PEs）。我们的目的是比较它们：（i）在安装于尤斯灌流室的离体大鼠肠黏膜和非外翻肠囊中作用机制，（ii）在这些模型以及原位空肠内灌注中对黏膜完整性的影响，以及（iii）与肠道黏液的相互作用。SNAC以浓度依赖方式增加了细胞旁标记物异硫氰酸荧光素葡聚糖4000（FD4）跨离体大鼠胃黏膜的表观渗透系数（P），而C则没有，同时两者都降低了跨上皮电阻（TEER）。在离体空肠和结肠黏膜中，两种药物都增加了[C]-甘露醇和FD4的P，而C降低了TEER，SNAC则没有。在空肠和结肠黏膜中，需要20 mM的SNAC才能达到10 mM C的效果。在离体非外翻空肠和结肠囊中，在两种PEs存在的情况下均观察到FD4通量增加。黏膜组织学显示，在增加通量的浓度下，两种PEs均对黏膜造成轻微上皮损伤。空肠组织对上皮损伤的耐受顺序为：原位空肠内灌注>空肠囊>离体空肠黏膜。两种PEs均调节了猪空肠黏液的粘弹性特性，而未改变其流变学特性。总之，SNAC和C在大鼠肠道组织中是相当有效的PEs，具有共同的总体作用机制特征。它们的效力和潜在毒性较低，与临床试验数据一致。
