Transport bile acid system

Several active transport systems that are normally found in the small intestinal enterocytes have been characterized in the Caco-2 cell model [13]. These include transport systems for glucose [32, 33], amino acids [34-37], dipeptides [38-40], vitamins [41], and bile acids [42, 43]. 

In addition to the passive diffusional processes over lipid membranes or between cells, substances can be transferred through the lipid phase of biological membranes through specialized systems, i.e., active transport and facilitated diffusion. Until recently, the active transport component has been discussed only for nutrients or endogenous substances (e.g., amino acids, sugars, bile acids, small peptides), and seemed not to play any major role in the absorption of pharmaceuticals. However, sufficient evidence has now been gathered to recognize the involvement of transporters in the disposition of pharmaceuticals in the body [50, 127]. 

Wess, G., Kramer, W., Han, X. B., Bock, K., Enhsen, A., Glombik, H., Baringhaus, K. H., Boger, G., Urmann, M., Hoffmann, A. et al., Synthesis and biological activity of bile acid-derived HMG-CoA reductase inhibitors. The role of 21-methyl in recognition of HMG-CoA reductase and the ileal bile add transport system, /. Med. Chem. 1994, 37, 3240-3246. 

Other Toxicity Concerns. Additional toxicity concerns include interference with normal metabolism and function of mucosal cells, for example, water absorption by these cells [80]. The unconjugated bile acids are known to block amino acid metabolism [81] and glucose transport [82]. There is a possibility of biotransformation of these enhancers to toxic or carcinogenic substances by hepatic monooxygenases [83]. Absorption of permeation enhancers into the systemic circulation can also cause toxicity, for example, azone [84] and hexamethylene lauramide [85] which are absorbed... 

Figure 4.13 Uptake of bile acids in the jejunum. Bile adds (BA) and cholesterol (C) are secreted from the liver, via the bile, into the duodenum. Cholesterol is transported back into the blood, from the enterocyte, within chylomicrons. The latter enter the lymphatic system (i.e. the lacteals). Bile acids are absorbed from the jejunum into the hepatic portal vein for re-uptake into the liver.

ASBT has a complex regulatory system reflecting the importance of this transporter to bile-acid pool size and bile-acid synthesis rates. Hepatic nuclear factor la (HNF-la) is necessary for expression of ASBT as knockout mice showed no expression and had defective bile-acid transport.Conversely, FXR-null mice showed no difference in expression of ASBT, showing that FXR plays no part in regulation of ASBT. In man, HNF-la controls baseline promoter activity of the ASBT gene as the minimal construct with full promoter activity was found to have 3 HNF-la binding sites. These authors also showed that the promoter construct bound peroxisome proliferator activated receptor a (PPARa)/9 cis retinoic acid receptor heterodimer, demonstrating a link between bile-acid absorption and hepatic lipid metabolism mediated by PPARa. 

The liver secretes about 1 L of bile daily. Bile flow and composition depend on the secretory activity of the hepatic cells that line the biliary canaliculi. As the bile flows through the biliary system of ducts, its composition can be modified in the ductules and ducts by the processes of reabsorption and secretion, especially of electrolytes and water. For example, osmotically active compounds, including bile acids, transported into the bile promote the passive movement of fluid into the duct lumen. In the gallbladder, composition of the bile is modified further through reabsorptive processes. 

Although bile acid conjugates with amino acids are normally excreted into bile, amino acid conjugates of xenobiotics are usually excreted into urine. Conjugation with endogenous amino acids facilitates urinary excretion because of the organic anion transport systems located in the kidney tubules. 

The most efficient rectal absorption enhancers, which have been studied, include surfactants, bile acids, sodium salicylate (NaSA), medium-chain glycerides (MCG), NaCIO, enamine derivatives, EDTA, and others [45 17]. Transport from the rectal epithelium primarily involves two routes, i.e., the paracellular route and the transcellular route. The paracellular transport mechanism implies that drugs diffuse through a space between epithelial cells. On the other hand, an uptake mechanism which depends on lipophilicity involves a typical transcellular transport route, and active transport for amino acids, carrier-mediated transport for (3-lactam antibiotics and dipeptides, and endocytosis are also involved in the transcellular transport system, but these transporters are unlikely to express in rectum (Figure 8.7). Table 8.3 summarizes the typical absorption enhancers in rectal routes. 

FIG. 1 Movement of cholesterol (CHOL) and bile acids (BA) between the liver and small intestine. CHOL and BA in the liver are secreted into the gallbladder where they are stored temporarily until a fat-containing meal causes their secretion into the intestinal lumen. BA are absorbed with high efficiency (95%) and are recycled back to the liver via the hepatic portal vein. CHOL is absorbed less efficiently (50-60%) and must be incorporated into lipoproteins (chylomicrons) for transport back to the fiver via the systemic circulation. Accumulation of CHOL in the liver can promote secretion of CHOL into plasma, thus increasing LDL-CHOL concentration. Loss of CHOL and BA in feces represents the primary route of CHOL elimination from the body. 

BSEP also known as sister-P-glycoprotein (SPGP) was originally cloned from pig liver (185). BSEP is localized on the canalicular membrane of hepa-tocytes and is responsible for the secretion of bile salts across the canalicular membrane into bile. BSEP appears to be the predominant bile salt efflux system for hepatocytes, and is a critical component in the enterohepatic circulation of bile acids. A number of mutations in the transporter were found to the basis for progressive familial intrahepatic cholestasis type 2 (PFIC2) (186-188). Mutations found in PFIC2 patients include frameshifts, missense mutations, and premature termination codons. Most PFIC2 patients lack immunohistochemically detectable BSEP in their liver. Recently, seven... 

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... 

Artificial analogues of the chloride transporter prodigiosin are effective symport HC1 carriers as exemplified in the model systems developed by the groups of Gale [39] and Davis [40], Biological inspiration is also behind another Cl- carrier. Cholic acid is a naturally occurring bile acid that functions as a surfactant in the intestine. Derivatives with three binding sites known as cholapods are able to transport isolated anions across lipid bilayers [41],... 

Bile acids are channelled from the sinusoids periportally via transport systems with low affinity and high capacity, and in the perivenous area via transport systems with high affinity and low capacity. The bile acids are therefore excreted with decreasing concentration from the periportal to the perivenous area. 

Circulation of the bile acids is guaranteed by several metabolic pump systems in such a way that they are also transported against a concentration gradient. (3, 11, 15,... 

All bile acid transport systems possess a high reserve capacity, the potential of which greatly exceeds the normal maximum secretion level. Bile acid cross-over from the enterohepatic into the peripheral circulation arises only in the case of massive disturbances in secretion (e.g. in cholestasis). The approx. 1% proportion of bile acids present in the peripheral system remains constant, both pre- and post-prandially. The first-pass elimination of bile acids from the portal blood reaches 70-90%, depending on their type and conjugation status. The bile acids have a half-life of 2-3 days. 

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