Exploitation of bile acid transport systems in prodrug design

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.

Figure 1

Structures of the most important bile acids and amino acid conjugates of cholic acid.

Scheme 1

Biosynthesis of bile acids from cholesterol according to ref. [18].

Scheme 1

Biosynthesis of bile acids from cholesterol according to ref. [18].

Figure 2

Enterohepatic circulation of bile acids [8].

Figure 3

A schematic representation of the bile salt carriers in human hepatocytes and enterocytes [2].

Scheme 2

Structures of potential bile acid derivatives. Drugs may be attached either directly or via spacer molecules at positions C₃, C₇, C₁₂, or C₂₄ [104].

Figure 4

Examples of bile acid-drug conjugates prepared by Kramer, Wess, et al. [19,104,105,106,107].

Figure 5

Structure of the C₃-conjugated NBD-l-(Ala)₄ derivative of taurocholate [111].

Scheme 3

Liver-specific HMG-CoA reductase inhibitors by combining with bile acid structural elements [117].

Figure 6

General structural formula of bile acid-peptide conjugates studied by Swaan et al. [100].

Figure 7

The structure of cholic acid analog of cosalane designed to improve the poor oral bioavailability of cosalane, an anti-HIV agent [126].

Figure 8

Structures of C₂-C₃ annulated bile acid pyrazoles conjugated with naproxen [128].

Figure 9

The chemical structures of Bamet-UD2 (left) and Bamet-D3 (right), respectively [144].

Figure 10

Structure of the prodrug acyclovir valylchenodeoxycholate [97,159].