Bowe C L, Mokhtarzadeh L, Venkatesan P, Babu S, Axelrod H R, Sofia M J, Kakarla R, Chan T Y, Kim J S, Lee H J, Amidon G L, Choe S Y, Walker S, Kahne D
Department of Chemistry, Princeton University, Princeton, NJ 08544, USA.
Proc Natl Acad Sci U S A. 1997 Oct 28;94(22):12218-23. doi: 10.1073/pnas.94.22.12218.
Hydrophilic drugs are often poorly absorbed when administered orally. There has been considerable interest in the possibility of using absorption enhancers to promote absorption of polar molecules across membrane surfaces. The bile acids are one of the most widely investigated classes of absorption enhancers, but there is disagreement about what features of bile acid enhancers are responsible for their efficacy. We have designed a class of glycosylated bile acid derivatives to evaluate how increasing the hydrophilicity of the steroid nucleus affects the ability to transport polar molecules across membranes. Some of the glycosylated molecules are significantly more effective than taurocholate in promoting the intestinal absorption of a range of drugs, showing that hydrophobicity is not a critical parameter in transport efficacy, as previously suggested. Furthermore, the most effective glycosylated compound is also far less damaging to membranes than the best bile acid absorption promoters, presumably because it is more hydrophilic. The results reported here show that it is possible to decouple absorption-promoting activity from membrane damage, a finding that should spark interest in the design of new compounds to facilitate the delivery of polar drugs.
亲水性药物口服给药时往往吸收不佳。利用吸收促进剂促进极性分子跨膜表面吸收的可能性已引发了广泛关注。胆汁酸是研究最为广泛的一类吸收促进剂，但对于胆汁酸促进剂的哪些特性导致其具有功效，仍存在分歧。我们设计了一类糖基化胆汁酸衍生物，以评估增加甾体核的亲水性如何影响跨膜转运极性分子的能力。一些糖基化分子在促进多种药物的肠道吸收方面比牛磺胆酸盐有效得多，这表明疏水性并非如先前所述是转运功效的关键参数。此外，最有效的糖基化化合物对膜的损伤也远小于最佳胆汁酸吸收促进剂，大概是因为它更具亲水性。此处报道的结果表明，有可能将吸收促进活性与膜损伤分离开来，这一发现应会激发人们对设计新化合物以促进极性药物递送的兴趣。
