scholarly journals A study of the physicochemical interactions between biliary lipids and chlorpromazine hydrochloride. Bile-salt precipitation as a mechanism of phenothiazine-induced bile secretory failure

1976 ◽  
Vol 153 (3) ◽  
pp. 519-531 ◽  
Author(s):  
M C Carey ◽  
P C Hirom ◽  
D M Small
Keyword(s):  
Bile Salt ◽  
Bile Salts ◽  
Water Soluble ◽  
Molar Ratio ◽  
Micellar Solutions ◽  
Membrane Phospholipids ◽  
Chlorpromazine Hydrochloride ◽  
Physicochemical Interactions ◽  
Cationic Detergents

Since chlorpromazine hydrochloride [2-chloro-10-(3-dimethylaminopropyl)-phenothiazine hydrochloride] is commonly implicated in causing bile-secretory failure in man and is secreted into bile, we have studied the physicochemical interactions of the drug with the major components of bile in vitro. Chlorpromazine hydrochloride molecules are amphiphilic by virtue of possessing a polar tertiary amine group linked by a short paraffin chain to a tricyclic hydrophobic part. At pH values below the apparent pK (pK'a 7.4) the molecules are water-soluble cationic detergents. We show that bile salts in concentrations above their critical micellar concentrations are precipitated from solution by chlorpromazine hydrochloride as insoluble 1:1 salt complexes. In the case of mixed bile-salt/phosphatidylcholine micellar solutions, however, the degree of precipitation is inhibited by the phospholipid in proportion to its mole fraction. With increases in the concentration of chlorpromazine hydrochloride or bile salt, micellar solubilization of the precipitated complexes results. Sonicated dispersions of the negatively charged phospholipid phosphatidylserine were also precipitated, but dispersions of the zwitterionic phospholipid phosphatidylcholine were not. Chlorpromazine hydrochloride efficiently solubilized these membrane phospholipids as mixed micellar solutions when the drug:phospholipid molar ratio reached 4:1. Polarizing-microscopy and X-ray-diffraction studies revealed that the precipitated complexes were amorphous and potentiometric studies confirmed the presence of a salt bond. Some dissociation of the complex occurred in the case of the most polar bile salt (Ks 0.365). As canalicular bile-salt secretion determines much of bile-water flow, we propose that complexing and precipitation of bile salts by chlorpromazine hydrochloride and its metabolites may be physicochemically related to the reversible bile-secretory failure produced by this drug.

scholarly journals Studies on the interactions between bile salts and food emulsifiers under in vitro duodenal digestion conditions to evaluate their bile salt binding potential

2019 ◽  
Vol 174 ◽  
pp. 493-500 ◽  
Author(s):  
Julieta N. Naso ◽  
Fernando A. Bellesi ◽  
Víctor M. Pizones Ruiz-Henestrosa ◽  
Ana M.R. Pilosof
Keyword(s):  
Bile Salt ◽  
Bile Salts ◽  
Binding Potential ◽  
Food Emulsifiers

Effect of intestinal resection on bile salt absorption in dogs

1965 ◽  
Vol 208 (2) ◽  
pp. 363-369 ◽  
Author(s):  
M. R. Playoust ◽  
Leon Lack ◽  
I. M. Weiner
Keyword(s):  
Bile Salt ◽  
Bile Salts ◽  
Enterohepatic Circulation ◽  
Sodium Taurocholate ◽  
Intestinal Resection ◽  
High Fat ◽  
Salt Absorption ◽  
Complete Failure ◽  
Fat Meal

The efficiency of intestinal absorption of bile salts was evaluated by studying the rate of disappearance of radioactivity from the bile of dogs after the intravenous administration of sodium taurocholate-24-C14. Bile was sampled through an indwelling tube in the gall bladder. One day after a high-fat meal normal dogs retained 48% of the radioactivity; dogs with resection of the jejunum retained 48%, whereas those with resection of the ileum retained only 3% in the bile. This is consistent with previous observations that the ileum is the site of bile salt absorption in vitro and in anesthetized animals. Animals with resection of the ileum exhibited significant steatorrhea; however, three-fourths of the ingested fat was absorbed in spite of almost complete failure to absorb bile salts. This indicates that fat and bile salts are not normally absorbed together. Elimination of enterohepatic circulation of bile salts by resection of the ileum contributes to the observed steatorrhea.

scholarly journals Purification, characterization and in vitro bile salt-binding capacity of polysaccharides from Armillaria mellea mushroom

2019 ◽  
Vol 37 (No. 1) ◽  
pp. 51-56 ◽  
Author(s):  
Chonghui Yue ◽  
Xiaodan Zang ◽  
Chao Chen ◽  
Liangwei Dong ◽  
Yanqiu Liu ◽  
...  
Keyword(s):  
Bile Salt ◽  
Bile Salts ◽  
Binding Capacity ◽  
Monosaccharide Composition ◽  
Composition Analysis ◽  
Enzymatic Extraction ◽  
Armillaria Mellea ◽  
Ethanol Precipitation ◽  
Ultrasound Assisted

The crude polysaccharides from Armillaria mellea were obtained with an ultrasound assisted enzymatic extraction and ethanol precipitation. Two polysaccharide fractions were obtained by ethanol precipitation, which were named AMP-1 and AMP-2. The results of the monosaccharide composition analysis indicated that AMP-1 was composed of mannose, rhamnose, glucose, galactose, arabinose and fucose and that AMP-2 was composed of mannose, rhamnose, glucose, galactose and fucose. Glucose and galactose were the main monosaccharide fractions. The protein and nucleic acid contents in AMP-1 and AMP-2 were detected by using ultraviolet and infrared spectroscopy. The bile salt-binding capacities of the polysaccharide samples were studied in vitro. In comparison with lentinan (LP), AMP-1 and AMP-2 showed increased bile salt-binding capacity. AMP-1 showed the highest binding capacity against all the bile salts. The findings presented in this study highlight the potential of the A. mellea polysaccharides as a natural hypolipidaemic agent.

scholarly journals Efflux Inhibitor Bicalutamide Increases Oral Bioavailability of the Poorly Soluble Efflux Substrate Docetaxel in Co-Amorphous Anti-Cancer Combination Therapy

Molecules ◽  
2019 ◽  
Vol 24 (2) ◽  
pp. 266 ◽  
Author(s):  
Adam Bohr ◽  
Thais Nascimento ◽  
Necati Harmankaya ◽  
Johan Weisser ◽  
Yingya Wang ◽  
...  
Keyword(s):  
Efflux Pump ◽  
Water Soluble ◽  
Oral Dosage ◽  
In Vitro Dissolution ◽  
Molar Ratio ◽  
Cancer Drugs ◽  
Efflux Pump Inhibitor ◽  
Anti Cancer ◽  
Amorphous Formulation

Many anti-cancer drugs are difficult to formulate into an oral dosage form because they are both poorly water-soluble and show poor permeability, the latter often as a result of being an intestinal efflux pump substrate. To obtain a more water-soluble formulation, one can take advantage of the higher solubility of the amorphous form of a given drug, whereas to increase permeability, one can make use of an efflux pump inhibitor. In this study, a combination of these two strategies was investigated using the co-amorphous approach, forming an amorphous mixture of two anti-cancer drugs, docetaxel (DTX) and bicalutamide (BIC). The efflux substrate, DTX, was combined with the efflux inhibitor, BIC, and prepared as a single phase co-amorphous mixture at a 1:1 molar ratio using vibrational ball milling. The co-amorphous formulation was tested in vitro and in vivo for its dissolution kinetics, supersaturation properties and pharmacokinetics in rats. The co-amorphous formulation showed a faster in vitro dissolution of both drugs compared to the control groups, but only DTX showed supersaturation (1.9 fold) compared to its equilibrium solubility. The findings for the co-amorphous formulation were in agreement with the pharmacokinetics data, showing a quicker onset in plasma concentration as well as a higher bioavailability for both DTX (15-fold) and BIC (3-fold) compared to the crystalline drugs alone. Furthermore, the co-amorphous formulation remained physically stable over 1.5 years at 4 °C under dry conditions.

scholarly journals Size-Dependent Photodynamic Activity of Gold Nanoparticles Conjugate of Water Soluble Purpurin-18-N-Methyl-D-Glucamine

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Byambajav Lkhagvadulam ◽  
Jung Hwa Kim ◽  
Il Yoon ◽  
Young Key Shim
Keyword(s):  
Gold Nanoparticles ◽  
A549 Cells ◽  
Water Soluble ◽  
Molar Ratio ◽  
Anticancer Efficacy ◽  
Molar Ratios ◽  
Size Dependent ◽  
Photodynamic Activity ◽  
Wavelength Absorption

Gold nanoparticles (GNPs) conjugates of water soluble ionic photosensitizer (PS), purpurin-18-N-methyl-D-glucamine (Pu-18-NMGA), were synthesized using various molar ratios between HAuCl4and Pu-18-NMGA without adding any particular reducing agents and surfactants. The PS-GNPs conjugates showed long wavelength absorption of range 702–762 nm, and their different shapes and diameters depend on the molar ratios used in the synthesis.In vitroanticancer efficacy of the PS-GNPs conjugates was investigated by MTT assay against A549 cells, resulting in higher photodynamic activity than that of the free Pu-18-NMGA. Among the PS-GNPs conjugates, the GNPs conjugate from the molar ratio of 1 : 2 (Au(III): Pu-18-NMGA) exhibits the highest photodynamic activity corresponding to bigger size (~60 nm) of the GNPs conjugate which could efficiently transport the PS into the cells than that of smaller size of the GNPs conjugate.

scholarly journals In Vitro Hypocholesterolemic Effect of Coffee Compounds

Nutrients ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 437
Author(s):  
Filipe Manuel Coreta-Gomes ◽  
Guido R. Lopes ◽  
Cláudia P. Passos ◽  
Inês M. Vaz ◽  
Fernanda Machado ◽  
...  
Keyword(s):  
Bile Salt ◽  
Bile Salts ◽  
Soluble Fiber ◽  
Hexane Extraction ◽  
Selective Precipitation ◽  
Food Ingredients ◽  
Espresso Coffee ◽  
Coffee Lipids ◽  
Cholesterol Solubility

(1) Background: Cholesterol bioaccessibility is an indicator of cholesterol that is available for absorption and therefore can be a measure of hypocholesterolemic potential. In this work, the effect of commercial espresso coffee and coffee extracts on cholesterol solubility are studied in an in vitro model composed by glycodeoxycholic bile salt, as a measure of its bioaccessibility. (2) Methods: Polysaccharide extracts from coffees obtained with different extraction conditions were purified by selective precipitation with ethanol, and their sugars content were characterized by GC-FID. Hexane extraction allowed us to obtain the coffee lipids. Espresso coffee samples and extracts were tested regarding their concentration dependence on the solubility of labeled 13C-4 cholesterol by bile salt micelles, using quantitative 13C NMR. (3) Results and Discussion: Espresso coffee and coffee extracts were rich in polysaccharides, mainly arabinogalactans and galactomannans. These polysaccharides decrease cholesterol solubility and, simultaneously, the bile salts’ concentration. Coffee lipid extracts were also found to decrease cholesterol solubility, although not affecting bile salt concentration. (4) Conclusions: Coffee soluble fiber, composed by the arabinogalactans and galactomannans, showed to sequester bile salts from the solution, leading to a decrease in cholesterol bioaccessibility. Coffee lipids also decrease cholesterol bioaccessibility, although the mechanism of action identified is the co-solubilization in the bile salt micelles. The effect of both polysaccharides and lipids showed to be additive, representing the overall effect observed in a typical espresso coffee. The effect of polysaccharides and lipids on cholesterol bioaccessibility should be accounted on the formulation of hypocholesterolemic food ingredients.

Comparison of In Vitro Binding of Bile Salt by Pectins from Various Sources

2012 ◽  
Vol 506 ◽  
pp. 274-277 ◽  
Author(s):  
K. Cheewatanakornkool ◽  
A. Chaidedgumjorn ◽  
U. Sotanaphun ◽  
S. Limsirichaikul ◽  
C. Wessapan ◽  
...  
Keyword(s):  
Bile Salt ◽  
Bile Salts ◽  
Serum Cholesterol Level ◽  
Sodium Deoxycholate ◽  
Sodium Cholate ◽  
Experimental Animals ◽  
Hypocholesterolemic Action ◽  
Acid Reaction ◽  
Layer Chromatography

Binding of bile salts by dietary fiber is believed to promote their excretion and hence to reduce the serum cholesterol level in man and experimental animals. In this study, the binding efficiency of soluble pectin from various sources, i.e., apple, citrus and pomelo, was examined. Sodium deoxycholate and sodium cholate hydrate were used as a model to represent bile salt in human body. The binding efficiency was assayed by acid reaction, thin layer chromatography (TLC) and enzyme cycling method. The results demonstrated that enzyme cycling method was the most suitable for assaying the in-vitro binding of bile salts while the TLC was not very sensitive, i.e., low amount of bile salts cannot be detected by TLC. Excess pectin from binding test could also interfere the acid reaction method even though the centrifugation was used to remove the excess pectin. When the concentration of pectin was increased, the binding efficiency with sodium deoxycholate increased. However, at 1% w/w of pectin, the binding efficiency decreased. The exception is for pomelo pectin in which the binding efficiency increased when the pectin concentration increased. With sodium cholate hydrate, only slight difference in binding efficiency was observed for all types and concentrations of pectin. The results indicate that the ability to bind bile salts of pectin might be responsible for its hypocholesterolemic action observed in experimental animals and humans.

Abstract 282: Murine Abcb1 Functions as an Efflux Transporter for Bile Salts After Chronic Administration of a Western Diet

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Stephen D Lee ◽  
Sheila J Thornton ◽  
Kishor M Wasan
Keyword(s):  
Bile Acid ◽  
Bile Salt ◽  
Bile Acids ◽  
Knockout Mice ◽  
Health Research ◽  
Bile Salts ◽  
Molar Ratio ◽  
Wild Type ◽  
Transport Pathway ◽  
Efflux Mechanism

Rationale: Removal of bile salts from the liver is the final step of the reverse cholesterol transport pathway. We studied the contribution of Abcb1 (P-glycoprotein), in bile acid efflux. Although a number of endogenous substrates have been postulated for Abcb1 based on in vitro evidence, studies using animal models have not supported these claims. Recent studies in mice demonstrated that in the absence of the Bile Salt Efflux Pump (Bsep), Abcb1 is required for removal of bile salts, especially when challenged with a cholic acid containing diet. To date, no study using atherogenic diets has demonstrated the role of Abcb1 in the removal of bile salts in the presence of functional Bsep. Methods: We fed male mice lacking both isoforms of Abcb1 (Abcb1a -/- /1b -/- ) and wild-type controls a diet providing either 25% or 45% of the kcal from fat, supplemented with either normal chow or high levels of cholesterol (0.02% w/w or 0.2% w/w respectively) for nine weeks; n=5 per group. On the tenth week, we assessed the efflux of cholesterol, phospholipid and bile acids to the gallbladder. Enzymatic assays were used to measure cholesterol and phospholipid, the pool of bile acids was quantified by HPLC to determine the concentrations of the six most prevalent murine bile acids. Results: Abcb1 knockout mice have a >30% reduction in the moles of bile salt normalized to phospholipid relative to wild type mice after administration of diets containing either elevated fat or cholesterol (p<0.05). Neither the efflux of phospholipid, nor the molar composition of the six bile acids was affected by deletion of Abcb1. Conclusions: We conclude that Abcb1 is a secondary efflux mechanism required for the removal of bile acids after consumption of diets rich in fat and/or cholesterol. Although Abcb1 knockout mice have reduced total bile acids in the gallbladder, the molar ratio of the specific bile acids is the same as in the wild type mice. These data suggest that Abcb1 effluxes the six bile acids in a non-specific manner, unlike Bsep which preferentially effluxes hydrophobic bile acids. The lack of specificity demonstrated by Abcb1 is desirable for a low- affinity secondary efflux mechanism, which supplements Bsep activity in bile acid output. Acknowledgments: Canadian Institutes of Health Research, Michael Smith Foundation for Health Research

scholarly journals The Emerging Role of Soluble Adenylyl Cyclase in Primary Biliary Cholangitis

2017 ◽  
Vol 35 (3) ◽  
pp. 217-223 ◽  
Author(s):  
Jung-Chin Chang ◽  
Ulrich Beuers ◽  
Ronald P.J. Oude Elferink
Keyword(s):  
Bile Salt ◽  
Adenylyl Cyclase ◽  
Barrier Function ◽  
Bile Salts ◽  
Primary Biliary Cholangitis ◽  
Biliary Cirrhosis ◽  
Bicarbonate Secretion ◽  
Soluble Adenylyl Cyclase ◽  
Induced Apoptosis

Background: Primary biliary cholangitis (PBC; previously referred to as primary biliary cirrhosis) is a chronic fibrosing cholangiopathy with the signature of an autoimmune disease and features of intrahepatic cholestasis. Immunosuppressing treatments are largely unsuccessful. Responsiveness to ursodeoxycholic acid and reduced expression of anion exchanger 2 (AE2) on canalicular membranes and small bile ducts underline the importance of bicarbonate transportation in its disease mechanism. Soluble adenylyl cyclase (sAC; ADCY10) is an evolutionarily conserved bicarbonate sensor that regulates apoptosis, barrier function and TNF signaling. Key Messages: The biliary epithelium defends against the toxic bile by bicarbonate secretion and by maintaining a tight barrier. Passive diffusion of weak acid conjugates (e.g. bile salts and other toxins) across plasma membrane is pH-dependent. Reduced AE2 expression results in both reduced bicarbonate secretion and accumulation of bicarbonate in the cells. Increased intracellular bicarbonate leads to increased sAC activity, which regulates bile salt-induced apoptosis. Reduced bicarbonate secretion causes more bile salts to enter cells, which further increase sAC activity by releasing intracellular Ca2+ store. In vitro studies demonstrate that inhibition of sAC not only corrects sensitization to bile salt-induced apoptosis as a result of AE2 down-regulation but also prevents bile salt-induced apoptosis altogether. Targeting sAC is also likely to slow down disease progression by strengthening the barrier function of biliary epithelia and by reducing oxidative stress as a result of chronic inflammation. Conclusions: sAC is a potential therapeutic target for PBC. More in vitro and in vivo studies are needed to understand how sAC regulates bile salt-induced apoptosis and to establish its therapeutic value in PBC and other cholestatic cholangiopathies.

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