Bile acids in drug discovery

Enhsen, Alfons; Kramer, Werner; Wess, G.

doi:10.1016/s1359-6446(96)10046-5

Cited by 145 publications

(137 citation statements)

References 30 publications

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“…Many waste products, including bile salts (which are not only digestive detergents but also end products of cholesterol metabolism), bilirubin (the end product of heme metabolism), cholesterol (derived from the synthesis and exceeding body needs) and heavy metals such as iron and copper (also derived from absorption exceeding body needs), are removed from the body by secretion into bile and eliminated via faeces [5]. For drug elimination, the biliary secretion pathway presents an excretory route for lipophilic steroids and drug metabolites [6]. Although every day large quantities of bile salts are secreted into the intestine, only moderate amounts are lost from the human body, because approximately 95 % of the bile salts delivered to the duodenum are reabsorbed into blood within the ileum.…”

Section: Introductionmentioning

confidence: 99%

Membranolytic Activity of Bile Salts: Influence of Biological Membrane Properties and Composition

et al. 2007

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Abstract:The two main steps of the membranolytic activity of detergents: 1) the partitioning of detergent molecules in the membrane and 2) the solubilisation of the membrane are systematically investigated. The interactions of two bile salt molecules, sodium cholate (NaC) and sodium deoxycholate (NaDC) with biological phospholipid model membranes are considered. The membranolytic activity is analysed as a function of the hydrophobicity of the bile salt, ionic strength, temperature, membrane phase properties, membrane surface charge and composition of the acyl chains of the lipids. The results are derived from calorimetric measurements (ITC, isothermal titration calorimetry). A thermodynamic model is described, taking into consideration electrostatic interactions, which is used for the calculation of the partition coefficient as well as to derive the complete thermodynamic parameters describing the interaction of detergents with biological membranes (change in enthalpy, change in free energy, change in entropy etc). The solubilisation properties are described in a so-called vesicle-to-micelle phase transition diagram. The obtained results are supplemented and confirmed by data obtained from other biophysical techniques (DSC differential scanning calorimetry, DLS dynamic light scattering, SANS small angle neutron scattering).

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Section: Introductionmentioning

confidence: 99%

Membranolytic Activity of Bile Salts: Influence of Biological Membrane Properties and Composition

et al. 2007

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“…They are stored in the gall bladder, secreted into the small intestine, and subsequently reabsorbed by both passive and active transport. This interesting feature to preserve the total amount of bile acids in the body (e.g., 2.5-5 g in human) is called the enterohepatic circulation, which is mediated by the high efficacy of both intestinal and liver absorptions (26). For the intestinal absorption of bile acids, ileum plays an important role because it possesses bile acid transporter that deliver bile acids to the liver via the portal vein.…”

Section: Bile Acids Binding To Bbmvmentioning

confidence: 99%

“…For the intestinal absorption of bile acids, ileum plays an important role because it possesses bile acid transporter that deliver bile acids to the liver via the portal vein. This active transport system has drawn a great attention for the use of bile acids as a potential drug carrier to augment the oral absorption and bioavailability of drugs (26)(27)(28).…”

Section: Bile Acids Binding To Bbmvmentioning

confidence: 99%

“…CA and its taurine conjugate (TCA) were chosen for the SPR analysis because they are main primary bile salts. DOCA, produced by the action of the intestinal bacteria, was also tested as a representative secondary bile salt (26,27). The binding events were observed from the surfaces of BBMVs, in which ileal and duodenal membranes were separately loaded onto different sensor channels.…”

Section: Bile Acids Binding To Bbmvmentioning

confidence: 99%

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Preparation and Characterization of Reconstructed Small Intestinal Brush Border Membranes for Surface Plasmon Resonance Analysis

Cho

Park

et al. 2004

Pharm Res

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Purpose. To prepare the surface generated by small intestinal brush border membrane vesicles (BBMVs) for the surface plasmon resonance (SPR) analysis, which allows the real-time measurement of binding events occurring on the intestinal membrane. Methods. BBMVs were isolated from Sprague-Dawley rats, suspended in HEPES-buffered saline, and flowed over the surface of a SPR sensor chip composed of dextran derivatives modified with lipophilic residues. The surface coverage was determined from binding of bovine serum albumin to BBMV-immobilized sensor chip. The performance of BBMVs immobilized was evaluated by their interaction with otilonium bromide and bile salts. Results. The stable BBMV surface was achieved when BBMV suspension was flowed over the sensor chip for 8 h at a rate of 2 l/min. The flow of otilonium bromide resulted in an increased SPR signal because of its binding to calcium channel, which is known to be distributed over the gastrointestinal tact. When bile salts were flowed over ileal and duodenal BBMV surfaces, respectively, a slightly higher SPR signal was observed in the ileal BBMV surface, indicating the specific interaction of bile salts with bile acid transporters. Conclusions. BBMV surfaces may be useful for the estimation of binding events on the intestinal membrane by SPR analysis, especially for the drugs that are orally administrated.KEY WORDS: surface plasmon resonance; intestinal brush border membrane; otilonium bromide; bile salts.

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“…[1][2][3][4][5][6][7] They also have pharmacological potential to act as carriers of liver-specific drugs, absorption enhancers, and as cholesterol-lowering agents, 8 which have made bile acids extensively studied compounds in chemistry and medicine. We have recently reported synthetic procedures for preparing a lithocholaphane 9 and steroidal molecular clefts containing three arylcarboxy, 10 isomeric pyridine-n-carboxy, 11 and isomeric n-acetoxyphenylcarboxy (acetylsalicylate and its isomers) 12 moieties and their complexation tendencies towards silver(I)-cation.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and 13C NMR chemical shift assignments of 2,2'-bipyridine-4,4'-dicarboxylates of bile acid methyl esters

Tamminen¹,

Kolehmainen²,

Haapala³

et al. 2000

Arkivoc

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Novel 2,2'-bipyridine-4,4'-dicarboxylates 3a-3d of four bile acid methyl esters have been synthesized from 2,2'-bipyridine-4,4'-dicarboxylic acid 1 and the corresponding bile acid methyl esters (methyl lithocholate 2a, methyl chenodeoxycholate 2b, methyl deoxycholate 2c, and methyl cholate 2d). In addition to the desired products, 3α -(2,6-dichlorophenylcarboxy) bile acid methyl esters 4a-4d were obtained. The structures of 3a-4d have been ascertained by 1 D 1 H and 13 C NMR, 2 D PFG 1 H, 13 C HMQC, and MALDI TOF MS. Molecular weights and 13 C NMR chemical shifts of 3a-4d have been presented. The geometry of 3a has been optimized semiempirically at the PM3 level and it has been observed that the minimum energy structure of 3a is a open type conformation due to lack of attractive intramolecular electrostatic interactions between the heads of the molecule which would have favoured the formation of cleft type structure. The synthesized bipyridine-bile acid conjugates are interesting structures from the molecular recognition point of view because they could have potential to form complexes with some transition metal ions, for example with silver, cadmium, and ruthenium.

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Bile acids in drug discovery

Cited by 145 publications

References 30 publications

Membranolytic Activity of Bile Salts: Influence of Biological Membrane Properties and Composition

Membranolytic Activity of Bile Salts: Influence of Biological Membrane Properties and Composition

Preparation and Characterization of Reconstructed Small Intestinal Brush Border Membranes for Surface Plasmon Resonance Analysis

Synthesis and 13C NMR chemical shift assignments of 2,2'-bipyridine-4,4'-dicarboxylates of bile acid methyl esters

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