Abstract
The enterohepatic circulation of bile acids is one of the most efficient recycling routes in the human body. It is a complex process involving numerous transport proteins, which serve to transport bile acids from the small intestine into portal circulation, from the portal circulation into the hepatocyte, from the hepatocyte into the bile, and from the gall bladder to the small intestine. The tremendous transport capacity and organ specificity of enterohepatic circulation combined with versatile derivatization possibilities, rigid steroidal backbone, enantiomeric purity, availability, and low cost have made bile acids attractive tools in designing pharmacological hybrid molecules and prodrugs with the view of improving intestinal absorption, increasing the metabolic stability of pharmaceuticals, specifically targeting drugs to organs involved in enterohepatic circulation, as well as sustaining therapeutically reasonable systemic concentrations of active agents. This article briefly describes bile acid transport proteins involved in enterohepatic circulation, summarizes the key factors affecting on the transport by these proteins, and reviews the use of bile acids and their derivatives in designing prodrugs capable of exploiting the bile acid transport system.
Highlights
Several potential drug molecules fail in the developmental phase, since they lack features that enable them to overcome barriers
Specific inhibition of the bile acid transporters is another important medical application [20]. This overview is aimed at highlighting the chemistry, biochemistry, and physiological functions of bile acids, their recirculation in the body and proteins involved in this complex process as well as factors affecting on the transport activity from the membrane protein-targeted prodrug design point of view not forgetting the fascinating examples of bile acid-containing prodrug applications
The efficiency and organ specificity of enterohepatic circulation of bile acids with numerous transport proteins is an intriguing target in designing prodrugs with a view of improving intestinal absorption, increasing the metabolic stability of pharmaceuticals, targeting drugs to organs involved in enterohepatic circulation, as well as sustaining therapeutically or prophylactically reasonable systemic concentrations of the active agents
Summary
Several potential drug molecules fail in the developmental phase, since they lack features that enable them to overcome barriers. Specific inhibition of the bile acid transporters is another important medical application [20] This overview is aimed at highlighting the chemistry, biochemistry, and physiological functions of bile acids, their recirculation in the body and proteins involved in this complex process as well as factors affecting on the transport activity from the membrane protein-targeted prodrug design point of view not forgetting the fascinating examples of bile acid-containing prodrug applications. A common structural feature of all natural bile acids is the cis configuration at C-5 combined with a pentanoic acid side chain attached to ring D. Their differences are determined by the number, position, and stereochemistry of the hydroxyl groups [8]. The order of acetylation, hydrolysis, vis-á-vis reduction, or hydrogenation is C3 > C7 > C12 [21]
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