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PubMed2002

Oral absorption of insulin encapsulated in artificial chyles of bile salts, palmitic acid and alpha-tocopherol dispersions.

The hypoglycemic effect of orally given insulin was studied on rabbits, using different bile salts as absorption promoters, in two different carriers to form an artificial chyloform system ready to be absorbed by intestinal mucosa. The rank order of enhancement by bile salts in the presence of 1% ethanol was deoxycholate>cholate>glycocholate>glycodeoxycholate>taurodeoxycholate>no bile salts. The dose response studies with increased insulin loaded in the chyle showed a greater corresponding hypoglycemic effect with the system of cholate-palmitic-alpha-tocopherol dispersions than the cholate-palmitic acid dispersions. A more effective hypoglycemic effect was achieved using lower doses of the deoxycholate-palmitate-tocopherol-chyle dispersions.

Administration, Oral↗
PubMed1987

Diabetes and intestinal cholesterol uptake from bile salt solutions.

A previously validated in vitro technique was used to determine the effect of diabetes mellitus on the intestinal uptake of cholesterol from various micellar bile salt solutions. The bile salts studied included cholic (C), taurocholic (TC), glycocolic (GC), chenodeoxycholic (CDC), taurochenodeoxycholic (TCDC), glycochenodeoxycholic (GCDC), deoxycholic (DC), taurodeoxycholic (TDC), and glycodeoxycholic (GDC). In control rats there was a reciprocal decline in cholesterol uptake with increasing concentrations of these nine bile acids, and cholesterol uptake was greater from the conjugated primary bile acids than from the unconjugated ones. With a 5 mM concentration of bile acids, the ratios of the uptake of 0.2 mM cholesterol in control rats were C = CDC = DC, TCDC greater than TC greater than TDC, and GC = GCDC greater than GDC; with 20 mM concentrations, the ratios of cholesterol uptake in control rats were C greater than CDC greater than DC, TC greater than TCDC greater than TDC, and GC = GCDC greater than GDC. In the diabetic animals cholesterol uptake was higher than in control rats when using 5 or 20 mM of each of the conjugated bile acids and with cholic acid. In contrast, cholesterol uptake was similar in diabetic and control animals when cholesterol was solubilized with 5 or 20 mM CDC or DC. These differences in cholesterol uptake using the various bile acids and the failure of CDC and DC to facilitate the enhanced uptake of cholesterol in diabetic animals remains unexplained.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1996

The interaction of pH, bile, and Helicobacter pylori may explain duodenal ulcer.

BACKGROUND: Inhibition of Helicobacter pylori growth by bile suggests that it should be difficult for H. pylori to colonize the duodenum and cause duodenal ulcer. To search for a common mechanism, we investigated the relationship between H. pylori strain (duodenal ulcer vs gastritis), type of bile acid conjugate, and inhibition of H. pylori growth. METHODS: H. pylori isolates from patients with duodenal ulcer and from volunteers with asymptomatic gastritis (six each) were grown in brain heart infusion broth medium containing mixtures of glycocholate, taurocholate, glycodeoxycholate, taurodeoxycholate, glycochenodeoxycholate, and taurochenodeoxycholate with and without lecithin. RESULTS: Synthetic human bile with or without lecithin inhibited H. pylori growth in a dose-dependent manner. There was no difference in inhibition between H. pylori gastritis and duodenal ulcer isolates. Glycine and mixed glycine and taurine-conjugated bile acids inhibited H. pylori more than taurine-conjugated bile acids (e.g., 51%, 67%, and 80% compared to 21%, 39%, and 46% for 1, 2, and 4 mM mixed conjugates compared with taurine conjugates, p < 0.05, respectively. CONCLUSIONS: The ability of H. pylori to grow in the presence of taurine-conjugated bile acids and the precipitation of glycine but not taurine bile acid conjugates by acid may provide one missing link among inhibition of H. pylori by bile, acid secretion, ability of antisecretory therapy to accelerate ulcer healing, and the ability of H. pylori to colonize the duodenal bulb of ulcer patients, leading to duodenal ulcer. These data also explain the disparate results of previous investigations of the effect of bile reflux in the stomach on the presence of H. pylori.

Bile↗
PubMed1990

The pH dependence of the hemolytic potency of bile salts.

The membrane damaging potential of dilute solutions of bile salts was evaluated by monitoring continuously the hemolysis of a small sample of red blood cells (RBC) introduced into a defined media containing the bile salts at various pH values. The strength of the hemolytic bile salt was characterized by the rate of the induced hemolysis and by the time that elapsed between the introduction of the RBC sample into the bile salt containing solution and the onset of hemolysis. The potency of the unconjugated bile acids was extremely sensitive to pH, e.g. the rate of hemolysis caused by a 7.5 mM cholate was 1.5%, 20% and 64% per min when the pH of the solution was 7.65, 7.3 and 6.85, respectively. At low pH values the membrane damaging effects of deoxycholate was clearly discerned at micromolar concentration range. The hemolytic potency of glycodeoxycholate was also enhanced significantly by lowering the pH. The taurine-conjugated cholate and deoxycholate were only slightly sensitive to variations in pH. Taurocholate at concentrations that were not hemolytic greatly enhanced the injurious potency of deoxycholate. These results imply that in acidic solutions the presence of bile acids can cause damage to cell membranes. It is suggested that the acidic environment in the proximal duodenum and acidosis developed during hypoxia in the liver are two situations in which the bile salts may constitute a pathogenic factor.

Animals↗
PubMed2001

The effect of absorption enhancers on the initial degradation kinetics of insulin by alpha-chymotrypsin.

The goal of this investigation was to establish a fast method to screen various insulin absorption enhancers by following their effect on the initial kinetics of insulin incubated with alpha-chymotrypsin at 37 degrees C. A simple, sensitive and reproducible reversed phase high performance liquid chromatography (HPLC) method has been developed to carry out this goal. Linear responses (r > 0.999) were observed over the range of 0.4-4 U/ml for insulin. There was no significant difference (P < 0.05) between inter- and intra-day studies for insulin. The mean relative standard deviations (RSD%) of the results of within-day precision and accuracy of insulin were 12%. The assay was sensitive to detect the existence of any metabolite due to the addition of any absorption enhancers, even if it was not seen with insulin alone. Three metabolites (A-C) were detected only when insulin was incubated with alpha-chymotrypsin at 37 degrees C. Metabolite D was observed when either glycocholic acid (0.5, 1%) or taurochenodeoxycholate (0.5, 1%) was incubated with insulin in the absence of alpha-chymotrypsin at 37 degrees C. The compounds that significantly increased insulin T50% were glycyrrhizic acid (0.5%) > deoxycholic acid (1%) > deoxycholic acid (0.5%) > glycyrrhizic acid (1%) > cholic acid (0.5, 1%). Capric acid (0.5%), hydroxypropyl-alpha-cyclodextrin (0.5, 1%) and dimethyl-alpha-cyclodextrin (0.5, 1, 5%) did not significantly affect insulin T50%. The bile salts increased insulin T50% in this order: deoxycholate > cholate > glycocholate > taurocholate > taurodeoxycholate > taurochenodeoxycholate > glycodeoxycholate. The results obtained would support the feasibility of utilizing such method for screening any compound incorporated in insulin formulation. These compounds should be used in the minimum possible concentration to avoid or minimize insulin degradation.

Absorption↗
PubMed1992

Fatty acid binding protein inhibits glycolithocholate sulfation.

Sulfation of hepatotoxic monohydroxy bile salts is viewed as an important detoxification mechanism. Bile salts are bound by fatty acid binding protein (FABP) with decreasing affinity as the extent of their hydroxylation increases. This binding has the potential to interfere with sulfation of monohydroxy bile salts and to augment their toxicity. FABP inhibits monohydroxy bile salt sulfation via bile salt sulfotransferases BST 1 and 2. With BST 1, the main BST, we obtained a maximal reduction of sulfation by 42.8 +/- 8.1%, using 10 microM glycolithocholate as substrate. FABP had no effect on sulfation of either 10 microM glycodeoxycholate or glycochenodeoxycholate. FABP may therefore specifically alter hepatotoxicity of lithocholate and its metabolites.

Animals↗
PubMed1994

Daily determination of individual serum bile acids allows early detection of hepatic allograft dysfunction.

Acute graft rejection is still a major cause of morbidity after orthotopic liver transplantation, and its diagnosis necessitates an invasive liver biopsy. Our aim has been to determine whether changes in individual serum bile acid levels after engraftment are sensitive, specific and reliable indicators of graft function and whether these changes can antedate other biochemical indicators of hepatic allograft rejection. Individual bile acids in 200 serum samples taken serially from eight adult liver transplant patients were measured. Patients with biopsy-confirmed graft dysfunction due to rejection or nonrejection causes (n = 6 episodes) had significantly higher serum concentrations of glycocholate plus glycochenodeoxycholate and taurocholate/taurochenodeoxycholate ratios than did noncomplicated grafts (n = 3). These changes antedated any other conventional biochemical parameters by at least 48 hr and were 100% sensitive and specific. None of the conventional liver function tests could match this. Acute rejection episodes (n = 3) were then compared with nonrejection causes of graft dysfunction (n = 3). In acute rejection we noted a significant increase in the concentration of glycodeoxycholate plus deoxycholate and a significant decrease in the cholate/chenodeoxycholate ratio compared with that in nonrejection graft malfunction. Both of these changes antedated any other biochemical parameters by 24 hr. In conclusion, individual serum bile acid assays, after orthotopic liver transplantation, can detect graft dysfunction resulting from any cause at an earlier time than routine biochemical tests, and they are sensitive, specific and reliable for early detection of graft dysfunction. In addition, acute rejection can be distinguished from other causes of graft dysfunction.

Adolescent↗
PubMed1979

The application of high pressure liquid chromatography to the analysis of bile salts in human bile.

Two high pressure liquid chromatography (HPLC) systems have been evaluated for the separation of conjugated bile salts from human bile. Partisil-10 ODS with mobile phase of methanol/water pH 2 (55 : 45) at 200 nm, 0.1 AUF UV detection gave only partial separation of bile salts. However, a mu Bondapak fatty acid analysis column using isopropanol/8.8 mmol/l potassium phosphate pH 2.5 (32 : 68) as the mobile phase and 193 nm, 0.1 AUF UV detection separated all the six conjugated bile salts in bile. The limit of detection ranged from 0.1 microgram for sodium taurocholate to 0.2 microgram for sodium glycodeoxycholate. The reproducibility and the application of the method to the analysis of conjugated bile salts was demonstrated using bile from five patients. Its application to the studies of hepato-biliary disease is discussed.

Bile↗
PubMedDate not supplied

12alpha- and 7alpha-hydroxysteroid dehydrogenase activities from Fusobacterium spp.

On screening fecal organisms for hydroxysteroid dehydrogenase activities applicable to bile acid metabolism studies, we have isolated a gram negative "Bacteroides-like" anaerobe which yields both 12alpha- and 7alpha-hydroxysteroid dehydrogenase (HSDH) activities in cell-free preparation. At the optimal harvest time of 36 hours, approximately 4500 units 12alpha-HSDH and 360 units 7alpha-HSDH were produced per 10(10) viable cells. The two enzymes appear to be separate entities in the basis of their stabilities on freezing, and prolonged storage at room temperature and elution volumes on Sephadex G 200. Thin layer chromatography studies on oxidation products confirmed the respective sites of oxidation to be the 12alpha-OH and 7alpha-OH position. No 3alpha-OH oriented activity was measurable. Preliminary kinetic studies of the 12alpha-HSDH revealed a broad pH curve with optimal activity at pH 9.5. Michaelis constants for glycodeoxycholate and NADP were estimated at 1.5 x 10(-4)M and 3.3 x 10(-5)M respectively.

Animals↗
PubMed1995

Role of amidation in bile acid effect on DNA synthesis by regenerating mouse liver.

Effect of bile acids on DNA synthesis by the regenerating liver was investigated in mice in vivo after partial hepatectomy (PH). Radioactivity incorporation into DNA after [14C]thymidine intraperitoneal administration peaked at 48 h after PH. At this time a significant taurocholate-induced dose-dependent reduction in DNA synthesis without changes in total liver radioactivity content was found (half-maximal effect at approximately 0.1 mumol/g body wt). Effect of taurocholate (0.5 mumol/g body wt) was mimicked by chocolate, ursodeoxycholate, deoxycholate, dehydrocholate, tauroursodeoxycholate, taurochenodeoxycholate, and taurodeoxycholate. In contrast, chenodeoxycholate, glycocholate, glycochenodeoxycholate, glycoursodeoxycholate, glycodeoxycholate, 5 beta-cholestane, bromosulfophthalein, and free taurine lacked this effect. No relationship between hydrophobic-hydrophilic balance and inhibitory effect was observed. Analysis by high-performance liquid chromatography indicated that inhibition of thymidine incorporation into DNA was not accompanied by an accumulation of phosphorylated DNA precursors in the liver but rather by a parallel increase in nucleotide catabolism. Bile acid-induced modifications in DNA synthesis were observed in vivo even in the absence of changes in toxicity tests, which suggests that the inhibitory effect shared by most unconjugated and tauroconjugated bile acids but not by glycoconjugated bile acids should be accounted for by mechanisms other than nonselective liver cell injury.

Animals↗
PubMed2000

In vitro/in vivo studies on a buccal bioadhesive tablet formulation of carbamazepine.

A buccoadhesive controlled-release system for delivery of carbamazepine (CBZ) was prepared by compression of hydroxypropyl methylcellulose (HPMC) and carbomer, incorporating a penetration enhancer, sodium glycodeoxycholate (GDC). The release behaviour of systems containing CBZ and various amounts of the two polymers with and without GDC was found to be non-Fickian. Formation of an interpolymer complex between HPMC and carbomer was confirmed in acidic medium by turbidity, viscosity and FT-IR measurements. Addition of the drug to the buccoadhesive formulation reduced the adhesion force significantly (p < 0.1). GDC did not have any effect on bioadhesion. Permeability of bovine buccal mucosa to CBZ was determined using Ussing diffusion chambers [1]. In vivo interaction between the tablet and tissue was examined histologically as well as by scoring mucosal irritation. Histological changes observed in the buccal epithelium after 4 h contact with the tablets containing GDC recovered completely within 24 h after removal. No measurable plasma level of CBZ was obtained either in the absence or presence of GDC.

Absorption↗
PubMed1975

Effect of bile salts on lactosylceramide beta-galactosidase activities in human brain, liver and cultured skin fibroblasts.

The effect of bile salts on the hydrolysis of lactosylcermide by human beta-galactosidases in vitro was studied using cultured skin fibroblasts, liver and brain tissue. The evidence for two distinct enzymes that can catalyze the hydrolysis of lactosylceramide was observed when the bile salt was changed from pure sodium taurocholate to either crude taurocholate, or pure glycodeoxycholate, taurodeoxycholate or taurochenodeoxycholate. Tissues from patients with Krabbe's disease were found to be deficient in lactosylceramide beta-galactosidase activity (lactosylceramidase I) when pure taurocholate was used in the assay. When crude taurocholate was used in the assay, the Krabbe patients appeared to have normal activity for this enzyme. In place of crude taurocholate the pure salts of glycodeoxycholate, taurodeoxycholate and taurochenodeoxycholate worked even better to stimulate the second lactosylceramide beta-galactosidase activity and GM1 gangliosidosis patients exhibiting little if any activity. Therefore, lactosylcermidase I is stimulated by crude taurocholate or pure glycodeoxycholate, taurodeoxycholate and taurochenodeoxycholate. The use of pure bile salts to assay lactosylceramidase I and II will result in better reproducibility for these enzyme activities between laboratories.

Bile Acids and Salts↗
PubMedDate not supplied

Application of 1H-n.m.r. to the design of liposomes for oral use. Synergistic activity of bile salts and pancreatic phospholipase A2 in the induced permeability of small unilamellar phospholipid vesicles.

H-n.m.r. spectroscopy of small unilamellar phospholipid vesicles in the presence of the lanthanide probe ion Dy3+ has been used to study the permeability of these liposomes induced by the bile salts (glycocholate and glycodeoxycholate) and pancreatic phospholipase A2. A marked synergism is demonstrated in the combined effects of these digestive agents in producing permeability of the vesicles to Dy3+. Changes in the 1H-n.m.r. spectrum of the vesicular phospholipid head-groups before permeability is induced, indicate that the products of the enzymic hydrolysis (lyso lipids and fatty acids) and transmembrane lipid exchange are involved in the permeability mechanism. The results are discussed in terms of the advantages of the use of n.m.r. techniques in the future design of liposomes for oral use.

Administration, Oral↗
PubMed2002

Examination of the solubilization of drugs by bile salt micelles.

The purpose of this review is to provide a critical examination of the reported solubilization of drugs by bile salt micelles. The underlying premise is that with better information regarding the inherent biological complexity, efforts to predict the oral bioavailability of drug will be enhanced. The common means of comparing the reported values was chosen to be the solubilization ratio. This is equal to the moles of drug solubilized per mole of bile salt. The values were segregated according to bile salt type, temperature, ionic strength, and the presence and absence of added lipids. Only segregation by bile salt type was pairwise statistically significant. From the solubilization ratios and the reported values of the aqueous solubility, the logarithms of the mole fraction micelle partition coefficients, log K(m/a), were calculated. The log K(m/w) was found to be correlated with the reported logarithm of the octanol/water partition coefficient. The rank order of slopes of the log K(m/a) as a function of log K(o/w) was cholate approximately taurodeoxycholate > glycocholate approximately taurocholate approximately glycodeoxycholate, with deoxycholate not being statistically different from the other data sets. The slope and intercept for the bile salt mixed micelle systems were 0.600 and 2.44, respectively, which were statistically indistinguishable from glycocholate, taurocholate, and glycodeoxycholate bile salt data. The existence of statistically significant correlations suggests that predicting the solubilization in the intestine may be possible with in vitro measurements if additional information is gathered in the appropriate micellar solutions.

Animals↗
PubMed1986

Bile salt-stimulated lipase in non-primate milk: longitudinal variation and lipase characteristics in cat and dog milk.

We report the presence of bile salt-stimulated lipase in milk collected from dog and cat. This enzyme has previously been found only in the milk of human and gorilla. Bile salt-stimulated lipase activity in individual dog milk specimens (range: 4.8-107.4 U/ml; 1 U = 1 mumol [3H]oleic acid released/min) was similar, while that in cat milk specimens (range: 2.2-16.9 U/ml) was lower than in human milk (range: 10-80 U/ml). Longitudinal patterns for bile salt-stimulated lipase activity differed depending upon the enzyme source: in dog milk, lipase activity was lowest in colostrum, while in cat milk, lipase activity was highest in colostrum and decreased at mid-lactation. In human milk, bile salt-stimulated lipase activity levels remain fairly constant throughout the first 3 months of lactation. Dog, cat and human milk bile salt-stimulated lipase activity had a neutral-to-alkaline pH optimum of 7.3-8.5, was stable at low pH (above 3.0 for at least 1 h), and was inhibited 95-100% by eserine (at concentrations greater than 0.6 mM). The lipase in the milk of the three species studied had an absolute requirement for primary bile salts (tauro- and glycocholate), and was inhibited by secondary bile salts (tauro- and glycodeoxycholate). These data are the first to report bile salt-stimulated lipase activity in milk from mammals other than the highest primates. Presence of this lipase in non-primate milk will permit the study of the factors that regulate the ontogeny, synthesis and secretion of the enzyme during pregnancy and lactation as well as its function in neonatal fat digestion.

Animals↗
PubMed1996

Mixed micelles of short chain alkyl surfactants and bile salts in electrokinetic chromatography: enhanced separation of corticosteroids.

The separation of a complex mixture of 17 corticosteroids was investigated by mixed micellar electrokinetic chromatography (MMEKC) employing various bile salts and/or alkylsulfonates. In this study, influence of individual surfactants and mixed micelles of hydrocarbon-bile salt surfactants on retention behavior, selectivity and the size of the elution window is investigated. Retention behavior of corticosteroids in SDS and bile salt micelles is examined using linear solvation energy relationships (LSER). In addition, the effects of type of bile salt surfactant on elution patterns were investigated. It was found that separation patterns are mostly influenced by the number of hydroxyl functional groups on the steroidal backbone of the bile salts, while the type of ionic head group has little, if any, effect on the steroids separation. Comparisons between mixed micellar techniques and the inclusion of conventional modifiers to various single and binary surfactant systems were made. The addition of modifiers such as acetonitrile, urea and beta-cyclodextrin to SDS surfactant systems, as well as mixed bile salt systems of sodium taurocholate and sodium glycodeoxycholate, did not improve the separation of the steroids. On the other hand, the addition of the short-chain alkylsulfonate sodium butanesulfonate to the mixture of taurocholate and glycodeoxycholate greatly improved the separation of the 17 corticosteroids and provided a baseline separation of all solutes. The effects of carbon chain length and concentration of alkylsulfonate on capacity factor, selectivity, efficiency and the size of the elution window were investigated.

Adrenal Cortex Hormones↗
PubMed1986

Biliary lipids support serum-free growth of Giardia lamblia.

Giardia lamblia has been grown in vitro only in media containing serum or serum fractions. How this pathogen can grow in the human small intestinal lumen without serum is not known. We found that samples of human hepatic or gall bladder bile maintained G. lamblia survival for 24 to 48 h in medium without serum but did not support growth. By contrast, an artificial biliary lipid dispersion containing six bile salts, phosphatidylcholine (PC), and cholesterol, in the ratios characteristic of human bile, supported parasite growth in medium without serum or serum fractions. To define the requirements, we showed that 1-palmitoyl-2-linoleoyl-PC or 1-palmitoyl-2-oleoyl-PC (which predominate in human bile) satisfied the requirement for PC. Moreover, either glycocholate or glycodeoxycholate could be substituted for the bile salt mixture. The finding that biliary lipids can support serum-free growth of G. lamblia may help explain why this parasite colonizes the upper small intestine.

Animals↗