The Apical Sodium-Dependent Bile Acid Transporter

The Apical Sodium-Dependent Bile Acid Transporter 

Studies with endogenous bile acids have led to a physiological understanding of the function of bile acid and the enterohepatic circulation. The search for a deeper understanding of the molecular mechanism behind the affinity and for recognition of molecules by the bile acid carriers in both ileum and liver motivated groups to modify bile acids and to study the carrier affinity of these compounds. These modifications typically entail either the substitution of the hydroxyl groups at the 3, 7, or 12 positions by other functionalities, or the addition to or alterations at the C-17 side chain. 

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Figure 2.3 Absorption of bile acids by the cholangiocyte in the cholehepatic shunt. Bile acids are absorbed at the apical membrane of the cholangioc5de by the apical sodium-dependent bile-acid transporter (ASBT) that causes cholehepatic shunting of bile acids back to the hepatocyte. Absorbed bile adds are exported across the basolateral membrane by multi-drug-resistance-associated protein 3 (MRP3), a truncated form of ASBT or by the het-eromeric organic solute (OST) a and p forms. Bile adds cause choleresis that is rich in bicarbonate ions secreted by the chloride/bicarbonate ion exchanger.

Exceptions from Lipinski s rule, i.e., molecules of PSA values > 140 A2 are found to be actively absorbed by carrier-mediated transport systems (Wessel et al. 1998), as shown in Fig. 3. IB. As further detailed in Fig. 3.2, the intestinal epithelium expresses a number of such transport systems for amino acids, organic anions and cations, nucleosides, and hexoses. Among these systems are the apical sodium-dependent bile acid transporter (ASBT Annaba et al. 2007), the monocarboxylate transporter (MCT Halestrap and Price 1999), the sodium-D-glucose co-transporter (SFGT1 Kipp et al. 2003), and the nucleotide transporter SPNT1 (Balimane and Sinko 1999). In addition, the expression of a specialized transporter system for small peptides has been found in the intestinal epithelium with the di/tripeptide transporter, PepTl (Tsuji 2002), after previous functional studies by Hu et al. (1989), and the cloning of PepTl... 

The Apical Sodium-Dependent Bile Acid Transporter (ASBT)... 

Chen, F., Ma, L., Dawson, P. A., Sinai, C. J., Sehayek, E., Gonzalez, F. J., Breslow, J., Ananthanarayanan, M., and Shneider, B. L. (2003) Liver receptor homologue-1 mediates species- and cell line-specific bile acid-dependent negative feedback regulation of the apical sodium-dependent bile acid transporter../. Biol. Chem. 278, 19909-19916. 

A series of novel benzothiepines (3R,3R -2,3,4,5-tetrahydro-5-aryl-l-benzothiepin-4-ol 1,1-dioxides) were synthesized by cyclization of arylsulfone aldehydes with KOBu. They are tested for their ability as apical sodium dependent bile acid transporter inhibitors <2005JMC5837, 2005JMC5853>. This class of benzothiepine is one of the most potent classes of inhibitors discovered to date. 

Balakrishnan, A., Sussman, D.J. and Polli, J.E. (2005) Development of stably transfected monolayer overexpressing the human apical sodium-dependent bile acid transporter (hASBT). Pharmaceutical Research, 22, 1269-1280. 

TL5956). Dihydrobenzothiazepine 205, derived from a two-step cyclocondensation process, underwent an iridium-catalyzed asymmetric hydrogenation reaction to afford, after chromatography, the desired diastereomer 206 (a late-stage intermediate in the synthesis of a benzothiazepinylphos-phonic acid found to be a nonabsorbable apical sodium-dependent bile acid transporter) (13JOC12726). 

The apical localized sodium-dependent bile add transporter (ASBT) is expressed in the human duodenum and ileum and is barely detectable in colon [16]. ASBT transports bile adds such as glycodeoxycholate and chenodeoxycholic add (XX) [49, 50]. Few examples exist where the bile acid scaffold has been used as a promoiety for a prodrug approach. ASBT has micromolar affinities for the natural substrates, and the studies on ASBT are too few to make a general statement on the potential and role of this transporter in drug absorption [49, 50]. 

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