Deoxycholic Acid Ratio Research Articles

Evaluation of 1β-Hydroxylation of Deoxycholic Acid as a Non-Invasive Urinary Biomarker of CYP3A Activity in the Assessment of Inhibition-Based Drug-Drug Interaction in Healthy Volunteers.

In this study, we aimed to evaluate the utility of endogenous 1β-hydroxy-deoxycholic acid/total deoxycholic acid ratio (1β-OH-DCA/ToDCA) in spot urine as a surrogate marker of cytochrome P450 3A (CYP3A) activity in the assessment inhibition-based drug–drug interactions in healthy volunteers. This was accomplished through an open-label, three-treatment parallel-arm study in healthy male volunteers from Zimbabwe. Each group received itraconazole (ITZ; 100 mg once daily; n = 10), fluconazole (FKZ; 50 mg once daily; n = 9), or alprazolam (APZ; 1 mg once daily; n = 8) orally. Midazolam (MDZ), dosed orally and intravenously, was used as a comparator to validate the exploratory measures of CYP3A activity and the effects of known inhibitors. Urinary metabolic ratios of 1β-OH-DCA/ToDCA before and after CYP3A inhibitor treatment showed a similar magnitude of inhibitory effects of the three treatments as that measured by oral MDZ clearance. The maximum inhibition effect of a 75% reduction in the 1β-OH-DCA/ToDCA ratio compared to the baseline was achieved in the ITZ group following six once-daily doses of 100 mg. The correlations of the two markers for CYP3A inhibitor treatment were significant (rs = 0.53, p < 0.01). The half-life of urinary endogenous 1β-OH-DCA/ToDCA was estimated as four days. These results suggested that 1β-OH-DCA/ToDCA in spot urine is a promising convenient, non-invasive, sensitive, and relatively quickly responsive endogenous biomarker that can be used for CYP3A inhibition-based drug–drug interaction in clinical studies.

Adriamycin-Incorporated Nanoparticles of Deoxycholic Acid-Conjugated Dextran: Antitumor Activity Against CT26 Colon Carcinoma

In this study, we prepared adriamycin (ADR)-encapsulated nanoparticles using deoxycholic acid-conjugated dextran (DexDA). Its antitumor activity was evaluated using CT 26 tumor cells in vitro and in vivo. ADR-incorporated DexDA nanoparticles have spherical shapes and their particle sizes were ranged about 50-200. Their particle sizes were changed according to the preparation conditions, i.e., the higher substitution degree (DS) of deoxycholic acid (DA) and higher drug feeding ratio induced increased particle size and zeta potential. Furthermore, the higher DS of DA and higher drug feeding ratio induced increased drug contents and loading efficiency of drug. The higher DS of DA and higher drug feeding ratio induced decreased drug release rate. Futhermore, acidic pH of release media accelerated the drug release rate compared to alkaline pH. At in vitro cytotoxicity test using CT26 tumor cells, the nanoparticles showed higher antitumor activity than free ADR. In fluorescence microscopic observation, nanoparticles were properly entered into tumors cells and maintained in the cells compared to ADR itself. At in vivo animal tumor model using CT-26 cells, nanoparticles resulted in survivability increase of mice even though free ADR showed higher effectiveness to inhibit tumor growth. These results suggested that ADR-incorporated DexDA nanoparticles are promising vehicles for anti-tumor drug delivery.

Doxorubicin release from self-assembled nanoparticles of deoxycholic acid-conjugated dextran

In this study, we synthesized deoxycholic acid (DA)-conjugated dextran (DexDA) and prepared doxorubicin (DOX)-encapsulated nanoparticles using DexDA conjugates. Since DexDA conjugates have amphiphilic properties, they will show self-aggregation behavior at aqueous environment. To approve self-aggregation behavior, critical aggregation concentration value of DexDA conjugates was evaluated using fluorescence spectroscopy. DOX-incorporated DexDA nanoparticles were less than 200 nm. The higher substitution degree of DA and higher drug feeding ratio resulted in increased particle size. Drug release was decreased by increase of substitution degree value of DA and increase of drug feeding ratio. At in vitro cytotoxicity test using DOX-resistant CT26 colon carcinoma cells, higher antitumor activity was obtained with DOX-incorporated nanoparticles compared to free DOX. Fluorescence microscopic observation verified this result, i.e. nanoparticles were properly entered into tumors cells and maintained longer compared to DOX itself. These results suggested that DOX-incorporated DexDA nanoparticles are promising vehicles for antitumor drug delivery.

Monolayers (Langmuir films) behavior of multi-component systems composed of a bile acid with different sterols and with their 1:1 mixtures

Different physicochemical properties of Langmuir films (monolayers) composed of 10 mixed systems of a bile acid, deoxycholic acid (DC) with various plant sterols, such as stigmasterol (Stig), β-sitosterol (Sito) and campesterol (Camp) and a stanol, cholestanol (Chsta) in addition to an animal sterol, cholesterol (Ch) [these sterols and Chsta are abbreviated as St] and DC with 1:1 St mixtures; (Ch + Chsta), (Ch + Stig), (Stig + Chsta), (Ch + Sito) and (Ch + Camp) on the substrate of 5 M aqueous NaCl solution (pH 1.2) at 25 °C, were investigated in terms of mean surface area per molecule ( A m), the partial molecular area (PMA), surface excess Gibbs energy (Δ G (ex)), interaction parameter ( I p) as well as activity coefficients ( f 1 and f 2) in 2-D phase of each binary (or ternary) component system and elasticity (Cs −1) of formed films; these were analyzed on the basis of the respective surface pressure ( π) versus A m isotherms as a function of mole fraction of Sts ( X st) in the DC/St(s) mixtures at discrete surface pressures. Notable findings are: (i) all the binary component systems did form patched film type monolayers consisting of (a) DC-dominant film solubilizing a trace amount of St molecules and (b) St dominant film dissolving a small amount of DC molecules, (ii) DC in 2-D phase exhibited a transition from LE film to LC film at a constant pressure ( π C 1 ) accompanied by compression and (iii) Δ G (ex) as well as I p was found to be greatly dependent on (a) the combinations of DC with different St species and (b) to be markedly varied by a difference in mixing ratio of DC to Sts. Compressibility (or elasticity) analyses and fluorescence microscopy images could support the above findings as well as interpretation.

Faecal pH, bile acid and sterol concentrations in premenopausal Indian and white vegetarians compared with white omnivores.

Faecal bulk, pH, water content, the concentrations of neutral sterols and bile acids and dietary intakes were measured in twenty-two Indian vegetarian, twenty-two white omnivorous and eighteen white vegetarian premenopausal women. Faecal bulk and water content were greater and pH lower in the Indian vegetarians. Total faecal animal sterol and coprostanol concentrations expressed on a dry-weight basis were lower in the vegetarians compared with the omnivores. The faecal sterol concentrations were correlated with dietary cholesterol intake. Primary bile acids were detected in six Indian vegetarians, two white vegetarians and two white omnivores; secondary bile acids were detected in all the white omnivores and vegetarian subjects but not in two of the Indian vegetarians. Total faecal free bile acid and conjugated bile acid concentrations were lower in the white vegetarians compared with the omnivores. Faecal lithocholic acid concentrations were lower in both Indian and white vegetarians. The lithocholic: deoxycholic acid ratio and coprostanol: total animal sterols ratio were significantly lower in the Indian vegetarians compared with the omnivores. Both ratios were positively correlated with faecal pH. Stepwise multiple regression analyses were undertaken in order to identify which nutrients influenced faecal pH, lithocholic and deoxycholic acid concentrations. The intakes of starch and dietary fibre were negatively associated with faecal concentrations of lithocholic and deoxycholic acid. Starch intake alone was negatively associated with faecal pH. The results of this study confirm that diets high in dietary fibre decrease faecal bile acid concentrations and suggest that the complex carbohydrates present in Indian vegetarian diets influence faecal pH and inhibit the degradation of faecal steroids.

Effects of rye bran, oat bran and soya-bean fibre on bile composition, gallstone formation, gall-bladder morphology and serum cholesterol in Syrian golden hamsters (Mesocricetus auratus)

The effects of rye bran, oat bran and soya-bean fibre on serum lipids, bile composition and gallstone formation were studied in male Syrian golden hamsters (Mesocricetus auratus). The control groups received fibre-free stone-provoking (O1 diet) or non-stone-provoking (O2 diet) diets. The serum cholesterol levels were lower for all groups fed on the diets supplemented with the dietary fibre sources compared with the control groups. The total content of bile acids in bile was higher in groups given rye-bran diets compared with the corresponding controls. The proportion of cholic acid was higher and that of chenodeoxycholic and lithocholic acid lower in the groups given rye-bran-, oat-bran- or soya-bean-fibre-supplemented diets, compared with the corresponding controls. The secondary:primary bile acid ratio was lower in the group given the rye-bran-supplemented O1 diet. The lithocholic:deoxycholic acid ratio was lower in the groups given rye-bran-, oat-bran- or soya-bean-fibre-supplemented diets than in the corresponding controls. A lower frequency of gallstones was observed only for the group receiving the rye-bran-supplemented O1 diet while the lithogenic index was lower in the groups given the rye-bran-supplemented O2 diet. A decreased epithelial volume density of the gall-bladder and an increased smooth muscular volume density were observed in animals given oat-bran- and rye-bran-supplemented O1 diets, whereas for the soya-bean-fibre-supplemented O1 diet, only the smooth muscular volume density was increased.