Design of compounds that increase the absorption of polar molecules

Abstract

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.

Determination of critical micellar concentrations of two monoketo derivatives of cholic acid

“…Such promotive action of bile acids is in correlation with their CMC values since the increase in the CMC leads to a decrease in the bile acid hydrophobicity and tendency to form micelles [9][10][11][12]. Bowe et al [9] suggested that an increased CMC means a lower membrane toxicity caused by the bile acid.…”

“…Some bile acids can act as promoters of the transport of certain drugs through the cell membranes [9][10][11]. Such promotive action of bile acids is in correlation with their CMC values since the increase in the CMC leads to a decrease in the bile acid hydrophobicity and tendency to form micelles [9][10][11][12].…”

A new drug carrier, N?-deoxycholyl-l-lysyl-methylester, for enhancing insulin absorption in the intestine

“…They are synthesized from cholesterol in the liver, from where they are carried via the bile duct to the small intestine, and return to the liver by absorption through the bile acid transporter [22,23]. The natural physicochemical properties and enterohepatic circulation of the bile acids suggest that these compounds could be used in the preparation of new drugs and formulations [24][25][26][27]. Using bile acid-based molecules, we developed a novel delivery agent that physically interacts with macromolecules to enable their oral absorption.…”

Antioxidant and Antimicrobial Activities ofPogostemon cablin(Blanco) Benth.

“…In previous report, the active hydroxyl groups of flavonoid are generally glycosylated. Glycosylation increases hydrophilicity of a molecule, which in its turn impairs its interaction with cellular membranes and decreases its rate of absorption [38,39]. Moreover, the literature showed flavonoids also effective scavengers of peroxyl, superoxide, and peroxynitrite radicals [40].…”