Exploitation of Bile Acid Transport Systems in Prodrug Design

Abstract

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.

MDCK Cells and Other Cell‐Culture Models of Oral Drug Absorption

“…In the terminal ileum, these compounds are actively taken up into the blood stream from where bile acids recirculate into the liver via the portal vein. The entire process is called as enterohepatic recirculation (Sievanen, 2007). These transporters are described as sodiumdependent sodium taurocholate cotransporting polypeptide (NTCP), organic anion transporting polypeptides (OATP-C, OATP8, and OATP-A), and apical sodium-dependent bile acid transporter (ASBT), and are ATP-dependent [bile salt export pump (BSEP)] (Balakrishnan and Polli, 2006).…”

Prodrug Strategies to Enhance Oral Drug Absorption

“…Active transport occurs near terminal ileum, following which the bile acids recirculate to the liver via the portal vein. This entire process is called enterohepatic recycling (Sievanen, 2007). They can be classified as follows: sodium-dependent (sodium/taurocholate cotransporting polypeptide or NTCP, organic anion transporting polypeptides OATP-C, OATP8, and OATP-A, and apical sodium-dependent bile acid transporter or ASBT) and ATP-dependent (bile salt export pump or BSEP) (Balakrishnan and Polli, 2006).…”

Impact of Impurity on Kinetic Estimates from Transport and Inhibition Studies

“…This suggests that some drugs with poor oral absorption may benefit from conjugation to bile acids by utilizing hASBT as carrier to enter the enterocyte. Despite the enormous potential of hASBT as target for bile acid containing prodrugs, only a few examples of its use can be found in the literature (Sievä nen, 2007). Employing this approach, the oral bioavailability of acyclovir was enhanced in rats via a bile acid conjugate prodrug of acyclovir (Tolle-Sander et al, 2004).…”