deoxycholic-acid and Body-Weight

The demand for aesthetic body sculpting procedures has expanded precipitously in recent years. Subcutaneous adipose tissue (SAT) deposits of the central abdomen are especially common areas of concern for both males and females.. To review the available literature regarding the underlying pathophysiology of subcutaneous fat accumulation in the abdominal area and available treatment options.. A MEDLINE and Google Scholar search was performed accordingly.. The preferential accumulation of SAT in the central abdomen is attributable to the reduced lipolytic sensitivity of its adipocytes. A number of therapeutic options are available for the treatment of central abdominal adiposity. Cryolipolysis, high-intensity focused ultrasound, nonthermal ultrasound, radiofrequency, and injection adipolysis lead to adipocyte destruction through multiple different mechanisms. Nonablative modalities such as injection lipolysis mobilize fat stores from viable adipocytes, although its effects may be curtailed in obese patients. Liposuction through tumescent technique, however, mechanically extricates SAT.. Although tumescent liposuction remains the gold standard for SAT removal, less invasive ablative and nonablative options for targeting localized deposits of adipose tissue now permeate the aesthetic marketplace. Limited results associated with these modalities mandate multiple sessions or combination treatment paradigms.

Topics: Adipocytes; Animals; Body Weight; Cryotherapy; Deoxycholic Acid; High-Intensity Focused Ultrasound Ablation; Humans; Lipectomy; Lipolysis; Low-Level Light Therapy; Radiofrequency Therapy; Subcutaneous Fat, Abdominal

In this study, rational dosing guidelines for amphotericin B-deoxycholate (AmB) are proposed for children. AmB steady-state trough concentrations (C(ss,trough)) and plasma creatinine concentrations (C(creat)) were measured in 83 children (age: 10 months to 18 years) receiving prophylactic AmB therapy (1 mg/kg/day). Maximum tolerable AmB C(ss,trough) were identified by determining the probability of large (>24%, 75th percentile) increases in C(creat) after 6 days of AmB for a series of C(ss,trough) ranges. Dose requirements were determined using a concentration-targeting approach. The 0.76-1.05 mg/l C(ss,trough) range provided the maximum concentrations that still had a low probability (p < 0.29) of adverse renal effects. 1 mg/kg/day AmB produces C(ss,trough) within this range for children weighing 25-45 kg. Lighter children (10-25 kg) require higher AmB doses (1.25-1.5 mg/kg/day) to achieve target C(ss,trough), while heavier children (45-55 kg) require lower doses (0.75 mg/kg/day). These starting dose guidelines may require individualization and prospective evaluation.

Topics: Adolescent; Amphotericin B; Antifungal Agents; Body Weight; Child; Child, Preschool; Computer Simulation; Creatinine; Cyclosporine; Deoxycholic Acid; Drug Combinations; gamma-Glutamyltransferase; Humans; Immunosuppressive Agents; Infant; Kidney Diseases; Microbial Sensitivity Tests; Models, Biological; Mycoses; Neoplasms; Risk Factors; Urea

The National Cooperative Gallstone Study was a double-masked trial conducted to determine the efficacy and safety of chenodeoxycholic acid (chenodiol) for dissolution of cholesterol gallstones. Patients with radiolucent gallstones were randomly allocated to either a high dose (750 mg/d, n = 305) or low dose (375 mg/d, n = 306) of chenodiol or placebo (n = 305) administered for 2 yr. Specimens of gallbladder bile were obtained for biliary lipid analysis on 50% of all white obtained for biliary lipid analysis on 50% of all white patients at base line and after 3-mo therapy, on 45% at 12 mo, and on 36% at 24 mo. Among these specimens, 20% were inadequate for analysis. For analysis of data, available values during therapy were averaged up to time of dissolution, study exit, or study termination. In the high-dose group, percent chenodiol (molar percent of all bile acids) increased markedly and remained high during the 2 yr of follow-up. Also, molar percent cholesterol decreased significantly and remained low during the 2 yr of follow-up. In the low-dose group, percent chenodiol increased and remained significantly increased. Percent cholesterol saturation decreased at 3 mo, but at 24 mo it was not different from that in the placebo group, suggesting a physiological adaptation to the low dose by 2 yr. 79% of patients on high dose had greater than 70% chenodiol. Among these, half showed unsaturated bile (less than 100% cholesterol saturation) while the remainder were supersaturated; in the former group with unsaturated bile, 23% had complete dissolution and 51% had partial (greater than 50% reduction in stone size) or complete dissolution. In contrast, those with over 70% chenodiol and supersaturated bile had only 5% complete dissolution. Thus, development of unsaturated bile was a major factor associated with gallstone dissolution. The data also indicate that values for percent cholesterol saturation were a better predictor of gallstone dissolution than molar percent chenodiol, although a high percent chenodiol usually was required to obtain unsaturation.

Topics: Bile; Body Weight; Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Clinical Trials as Topic; Deoxycholic Acid; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Lipid Metabolism; Lithocholic Acid; Male

Obese subjects are prone to supersaturated bile, which is maintained or increased during weight loss. In this report, two related studies were carried out on obese subjects to investigate effects of bile acid feeding on biliary lipid metabolism before and during weight reduction. In one study, chenodeoxycholic acid (CDCA), 750 mg/day, was given to 12 obese subjects during weight maintenance (1st mo) and during weight reduction (2nd mo). In the second study, effects of two bile acid preparations, CDCA and Bilron (containing mostly cholic acid and deoxycholic acid), randomly administered, were compared in another 12 obese subjects undergoing weight reduction. The results show that obese subjects had large pools of bile acids during weight maintenance which decreased on caloric restriction (1,000 kcal/day). CDCA increased pool size only modestly during weight maintenance, from 3,536 +/- 1,267 (SD) mg to 4,735 +/- 1,434 mg. Both CDCA and Bilron markedly reexpanded the contracted pool of bile acids in obese subjects on weight reduction. However, significantly reduced saturation of bile occurred only in those on CDCA and weight reductions, whereas supersaturation was unaltered when weight was maintained constant in these patients, or when Bilron was given. No significant side effects were noted during bile acid feeding for any of the subjects. Thus, CDCA given to obese subjects on weight reduction will reduce bile saturation and could protect against gallstones.

Topics: Adult; Bile; Bile Acids and Salts; Body Weight; Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Deoxycholic Acid; Diet, Reducing; Humans; Lipid Metabolism; Male; Middle Aged; Obesity; Triglycerides

Previous studies showed glucose and insulin signaling can regulate bile acid (BA) metabolism during fasting or feeding. However, limited knowledge is available on the effect of calorie restriction (CR), a well-known anti-aging intervention, on BA homeostasis. To address this, the present study utilized a "dose-response" model of CR, where male C57BL/6 mice were fed 0, 15, 30, or 40% CR diets for one month, followed by BA profiling in various compartments of the enterohepatic circulation by UPLC-MS/MS technique. This study showed that 40% CR increased the BA pool size (162%) as well as total BAs in serum, gallbladder, and small intestinal contents. In addition, CR "dose-dependently" increased the concentrations of tauro-cholic acid (TCA) and many secondary BAs (produced by intestinal bacteria) in serum, such as tauro-deoxycholic acid (TDCA), DCA, lithocholic acid, ω-muricholic acid (ωMCA), and hyodeoxycholic acid. Notably, 40% CR increased TDCA by over 1000% (serum, liver, and gallbladder). Interestingly, 40% CR increased the proportion of 12α-hydroxylated BAs (CA and DCA), which correlated with improved glucose tolerance and lipid parameters. The CR-induced increase in BAs correlated with increased expression of BA-synthetic (Cyp7a1) and conjugating enzymes (BAL), and the ileal BA-binding protein (Ibabp). These results suggest that CR increases BAs in male mice possibly through orchestrated increases in BA synthesis and conjugation in liver as well as intracellular transport in ileum.

Topics: Animals; Bile Acids and Salts; Blood Glucose; Body Weight; Caloric Restriction; Carrier Proteins; Cholesterol 7-alpha-Hydroxylase; Cholic Acids; Deoxycholic Acid; Dose-Response Relationship, Drug; Enterohepatic Circulation; Homeostasis; Intestines; Lipids; Liver; Male; Mice; Mice, Inbred C57BL; RNA, Messenger; Tandem Mass Spectrometry

The time course of tissue distribution of amphotericin B (AmB) has not been sufficiently characterized despite its therapeutic importance and an apparent disconnect between plasma pharmacokinetics and clinical outcomes. The goals of this work were to develop and evaluate a physiologically based pharmacokinetic (PBPK) model to characterize the disposition properties of AmB administered as deoxycholate formulation in healthy rats and to examine the utility of the PBPK model for interspecies scaling of AmB pharmacokinetics. AmB plasma and tissue concentration-time data, following single and multiple intravenous administration of Fungizone® to rats, from several publications were combined for construction of the model. Physiological parameters were fixed to literature values. Various structural models for single organs were evaluated, and the whole-body PBPK model included liver, spleen, kidney, lung, heart, gastrointestinal tract, plasma, and remainder compartments. The final model resulted in a good simultaneous description of both single and multiple dose data sets. Incorporation of three subcompartments for spleen and kidney tissues was required for capturing a prolonged half-life in these organs. The predictive performance of the final PBPK model was assessed by evaluating its utility in predicting pharmacokinetics of AmB in mice and humans. Clearance and permeability-surface area terms were scaled with body weight. The model demonstrated good predictions of plasma AmB concentration-time profiles for both species. This modeling framework represents an important basis that may be further utilized for characterization of formulation- and disease-related factors in AmB pharmacokinetics and pharmacodynamics.

Topics: Amphotericin B; Animals; Antifungal Agents; Body Weight; Deoxycholic Acid; Drug Combinations; Half-Life; Humans; Injections, Intravenous; Male; Mice; Models, Biological; Rats; Rats, Sprague-Dawley; Species Specificity; Tissue Distribution

The present study reports on the preparation and testing of a desoxycholate amphotericin B (D-AMB) sustained delivery system based on poly(lactic-co-glycolic acid) (PLGA) and dimercaptosuccinic acid (DMSA) polymeric blends (Nano-D-AMB) aimed at reducing the number of AMB administrations required to treat mycosis.. BALB/c mice were infected with the yeast Paracoccidioides brasiliensis intravenously to mimic the chronic form of paracoccidioidomycosis. At 30 days post-infection, the animals were treated with Nano-D-AMB [6 mg/kg of encapsulated D-AMB, intraperitoneally (ip), interval of 72 h] or D-AMB (2 mg/kg, ip, interval of 24 h). Drug efficacy was investigated by the fungal burden recovery from tissues. Toxicity was assessed by renal and hepatic biochemical parameters, physical appearance of the animals and haematological investigation. The control groups used were non-infected and the infected mice mock treated with PBS.. Nano-D-AMB presented results comparable to free D-AMB, with a marked antifungal efficacy. The Nano-D-AMB-treated group presented lower loss of body weight and absence of stress sign (piloerection and hypotrichosis) observed after D-AMB treatment. No renal [blood urea nitrogen (BUN), creatinine] or hepatic (pyruvic and oxalacetic glutamic transaminases) biochemical abnormalities were found. The micronucleus assay showed no significant differences in both the micronucleus frequency and percentage of polychromatic erythrocytes for Nano-D-AMB, indicating the absence of genotoxicity and cytotoxic effects.. The D-AMB-coated PLGA-DMSA nanoparticle showed antifungal efficacy, fewer undesirable effects and a favourable extended dosing interval. Nano-D-AMB comprises an AMB formulation able to lessen the number of drug administrations. Further studies would elucidate whether Nano-D-AMB would be useful to treat systemic fungal infections such as paracoccidioidomycosis, candidiasis, aspergillosis and cryptococcosis.

Topics: Amphotericin B; Animals; Body Weight; Bone Marrow; Colony Count, Microbial; Deoxycholic Acid; Drug Combinations; Female; Kidney; Lactic Acid; Liver; Lung; Mice; Mice, Inbred BALB C; Nanoparticles; Paracoccidioides; Paracoccidioidomycosis; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Succimer; Treatment Outcome

Prolonged large bowel transit, and an increase in the proportion of deoxycholic acid (DCA), have been implicated in the pathogenesis of cholesterol gallstones-including those developing in acromegalics treated with octreotide. However, there are few data on the effects of intestinal transit on bile acid kinetics.. We therefore measured the kinetics of DCA and cholic acid (CA) using stable isotopes, serum sampling, and mass spectrometry. The results were related to mouth-to-caecum (MCTT) and large bowel transit times (LBTTs) in 4 groups of 8 individuals: (1) non-acromegalic controls, (2) acromegalics untreated with octreotide, (3) acromegalics on long-term octreotide, and (4) patients with constipation. Paired, before and during octreotide, studies were performed in 5 acromegalics.. In the unpaired and paired studies, octreotide significantly prolonged MCTT and LBTT. In the paired studies, the octreotide-induced prolongation of LBTT caused an increase in the DCA input rate (6.4 +/- 2.8 to 12 +/- 2.6 micromol. kg. d, P < 0.05) and pool size (18 +/- 12 to 40 +/- 13 micromol/kg, P < 0.05), and a decrease in CA pool size (45 +/- 15 to 25 +/- 11 micromol/kg, P < 0.05). Furthermore, during octreotide treatment, the mean conversion of 13C-CA to 13C-DCA (micromoles) was greater (P < 0.05) on study days 3, 4, and 5. There were also positive linear relationships between LBTT and DCA input rate (r = 0.78), pool size (r = 0.82, P < 0.001), and a weak (r = -0.49) negative linear relationship between LBTT and CA pool size (P < 0.01).. These data support the hypothesis that, by increasing DCA formation and absorption, prolongation of large bowel transit is a pathogenic factor in the formation of octreotide-induced gallstones.

Topics: Acromegaly; Adult; Aged; Body Weight; Carbon Isotopes; Cholic Acid; Colon; Deoxycholic Acid; Deuterium; Female; Humans; Male; Middle Aged; Octreotide; Postprandial Period

To elucidate the role of fecal steroids in the malignant tumor formation of colonic epithelial cells, we examined the effects of dietary deoxycholic acid (DCA) and cholesterol (CHL) on fecal steroid concentrations and their impact on colonic crypt cell proliferation. Twenty 5-week-old male Fischer 344 rats were provided with either a control semisynthetic diet or the same diet supplemented with 0.15% DCA and 1% CHL (steroid diet) over a 5-week period. The effects of these two diets were compared among rats that were either injected with azoxymethane (AOM), a known gastrointestinal carcinogen, or saline. In a 2 x 2 factorial design, rats fed each of these diets were given two weekly subcutaneous injections of either AOM (15 mg/kg b.w.) or saline at 6 and 7 weeks of age. At 9 weeks of age, fecal samples were obtained for analysis of bile acids, CHL and its bacterial metabolites of intestinal microflora. At 10 weeks of age, animals were sacrificed and colonic proliferation was assessed as vincristine-accumulated mitotic figures per crypt. Rats fed the steroid diet had significantly elevated fecal bile acid (5x, P < 0.001) and neutral steroid (10x, P < 0.01) levels when compared to those fed the control diet. AOM treatment did not appear to influence these levels. However, rats injected with AOM had a significant increase (P < 0.001) in their rate of colonic cell proliferation as compared to saline-injected control animals on both diets. Furthermore, rats fed the steroid diet had a significantly higher (P < 0.001) cell proliferation rate than animals fed the control diet. The effects of AOM treatment and the steroid diet on cell proliferation were additive. Our results demonstrate that high concentrations of neutral and acid steroids in the colonic lumen can enhance carcinogen-induced elevated cell proliferation and thus may play a key role in the etiology of colon cancer.

Topics: Animals; Azoxymethane; Bile Acids and Salts; Body Weight; Carcinogens; Cell Division; Cholesterol, Dietary; Cocarcinogenesis; Colon; Colonic Neoplasms; Deoxycholic Acid; Eating; Feces; Male; Precancerous Conditions; Rats; Rats, Inbred F344; Steroids

Primary and secondary bile acids such as cholic (CHA), deoxycholic (DCA) and lithocholic (LCA) acids have been shown to increase colon tumorigenesis. It has been suggested that inhibition of xenobiotic metabolizing enzymes such as glutathione S-transferase (GST) and UDP-glucuronyltransferase (UGT) by bile acids may be a factor in the development of colon cancer. While enzyme inhibition has been demonstrated in vitro, it is unclear whether feeding bile acids modulates colonic GST and UGT in vivo. To test this notion, male, Sprague-Dawley rats (n = 100) were assigned to a control (CON) or test diets containing 0.2% CHA, DCA, LCA or ursodeoxycholic acid (UDCA). After 5 weeks, colonic tissue was harvested and used for enzyme and cell proliferation measurements. The response to bile acids varied with the enzyme measured and appeared isoenzyme specific. GST-alpha activity was lower in the bile acid fed groups compared with CON. While GST-mu was lower in the LCA-fed group, GST-pi was lower in the DCA-, CHA- and UDCA-fed groups. Unlike GST, both UGT and NADPH-cytochrome P-450 reductase (CYC) activities were increased by bile acids. The proliferative response of the colonic epithelium varied with the bile acids and was regionally specific. These data demonstrate that feeding bile acids alters the activity of colonic phase I and II enzymes; however, the physiological effect of these enzymatic perturbations is yet to be determined.

Topics: Animals; Body Weight; Cell Division; Cholagogues and Choleretics; Cholic Acid; Cholic Acids; Colon; Deoxycholic Acid; Diet; Eating; Glucuronosyltransferase; Glutathione Transferase; Lithocholic Acid; Male; Microsomes; NADPH-Ferrihemoprotein Reductase; Proliferating Cell Nuclear Antigen; Rats; Rats, Sprague-Dawley; Ursodeoxycholic Acid

We investigated the effects of bile acid feeding on the mRNA levels and transcriptional activity of genes involved in various facets of hepatic cell function. Rats were maintained for 10 days on standard diet supplemented with combinations of 1 and 0.4% deoxycholic acid and ursodeoxycholic acid. Significant reductions in mRNA levels for liver fatty acid binding protein, albumin, the asialoglycoprotein receptor, connexins 32 and 26, and cytochromes P-450IIB1 and P-450IIE1 were associated with 1% deoxycholic acid feeding. Conversely, the 1% deoxycholic acid-fed animals exhibited increased mRNA levels for cholesterol 7 alpha-hydroxylase, 3-hydroxy-3-methylglutaryl-CoA reductase, multidrug resistance, procollagens, extracellular matrix, protooncogenes, tumor suppressors, and cyclins. The 0.4% deoxycholic acid-fed animals exhibited increased mRNA levels for c-jun, H-ras, p53, cyclins D1 and D3, fibronectin, and procollagens alpha 1(I) and alpha 1(III). Transcriptional rate changes could not account for the observed changes in steady-state mRNA levels. Ursodeoxycholic acid feeding had no significant effect on gene expression and almost completely inhibited the changes associated with 1% deoxycholic acid when coadministered. The results indicate that dietary ingestion of deoxycholic acid profoundly affects hepatic gene expression in the rat, and regulation occurs primarily at the posttranscriptional level.

Topics: Animals; Bile Acids and Salts; Body Weight; Deoxycholic Acid; Diet; Gene Expression; Liver; Male; Organ Size; Rats; Rats, Sprague-Dawley; RNA, Messenger; Transcription, Genetic

The effects of gomisin A, a lignan component of Schizandra fruits, on the promotion stage of hepatocarcinogenesis initiated by 3'-methyl-4-dimethylamino-azobenzene (3'-MeDAB) in male Donryu rats were investigated. When different types of tumor promotors, phenobarbital (PB) and deoxycholic acid (DCA), were administered for 5 weeks after initiation by 3'-MeDAB, preneoplastic alterations in the liver, determined by glutathione S-transferase placental form (GST-P), were markedly increased. Gomisin A significantly inhibited the increase in number and size of GST-P positive foci, regardless of the promotor. This lignan inhibited the increase in serum bile acid concentration by administration of DCA, but hardly influenced the serum bile acids in the PB-combined group. These results suggest that the inhibitory effect of gomisin A on the promotive action of DCA is based on improving bile acid metabolism, but regarding the action of PB, the effect could not be elucidated from the metabolism of bile acids.

Topics: Animals; Anticarcinogenic Agents; Bile Acids and Salts; Body Weight; Carcinogens; Cyclooctanes; Deoxycholic Acid; Dioxoles; Immunohistochemistry; Lignans; Liver Neoplasms, Experimental; Male; Methyldimethylaminoazobenzene; Organ Size; Phenobarbital; Rats

This study was performed to clarify the promoting effects of primary or secondary bile acid load on the occurrence of cholangiocarcinoma, using Syrian golden hamsters. These hamsters received subcutaneously diisopropanolnitrosamine (DIPN) once weekly for 10 weeks, and simultaneously were given a standard pellet diet (control group) containing taurocholic acid (TCA group) or deoxycholic acid (DCA group). The rates of cholangiocarcinoma at 20 weeks were 23% in the control group, 60% in the TCA group and 59% in the DCA group. There were significant differences between the control and the TCA or DCA groups (p < 0.05). The rates of proliferation of bile ductules or hyperplasia of the bile duct epithelium and the bromodeoxyuridine labeling indices of bile duct epithelial cells were high in both groups treated with bile acids, compared with those in the control group. Regarding the composition of bile acids in the intraductal bile, the TCA and DCA groups revealed a decrease in primary bile acids and an increase in DCA. These results suggest that both TCA and DCA given orally promote the occurrence of DIPN-induced cholangiocarcinoma.

Topics: Adenoma, Bile Duct; Animals; Bile Duct Neoplasms; Body Weight; Carcinogens; Cocarcinogenesis; Cricetinae; Deoxycholic Acid; Eating; Liver; Male; Mesocricetus; Mitotic Index; Nitrosamines; Taurocholic Acid

The initiating potential of the secondary bile acids, deoxycholic acid (DCA) and lithocholic acid (LCA), for rat hepatocarcinogenesis was investigated using the development of hyperplastic nodules and/or glutathione S-transferase placental form (GST-P)-positive liver foci as the end point. Five week old male F344 rats were given either basal diet, or diets containing 0.5% DCA or 0.5% LCA for 3 weeks in conjunction with partial hepatectomy performed midway, followed by a selection regimen consisting of 2 weeks feeding of 0.02% 2-acetylaminofluorene diet and a single gastric intubation of carbon tetrachloride. The animals were then placed on either basal diet or a diet containing 0.05% phenobarbital (PB) for 52 weeks. Significantly higher numbers of hyperplastic liver nodules developed in the DCA-treated rats irrespective of PB promotion as compared with the respective control groups. No such increase was evident in the LCA-treated rats. In contrast, both DCA and LCA treatments enhanced the development of GST-P-positive liver foci with or without subsequent PB promotion. Only one hepatocellular carcinoma was diagnosed in a control group animal. The present data indicate that a short period of feeding of DCA and LCA in the initiation stage in conjunction with partial hepatectomy results in enhanced development of preneoplastic liver lesions under selection pressure conditions with or without subsequent PB promotion. They thus confirm and extend our previous finding of enhanced gamma-glutamyltranspeptidase-positive liver foci development in a short-term assay of DCA and LCA, and suggest that these secondary bile acids either possess possible initiating activity or some other priming effect for rat hepatocarcinogenesis.

Topics: Animals; Body Weight; Deoxycholic Acid; gamma-Glutamyltransferase; Glutathione Transferase; Lithocholic Acid; Liver Neoplasms, Experimental; Male; Phenobarbital; Precancerous Conditions; Rats; Rats, Inbred F344

The effect of dietary administration of four different amino acid (N-acyl) conjugates of ursodeoxycholic acid on biliary bile acid composition, liver tests and hepatic morphology by light microscopy was examined in the rabbit. Each group of four to five rabbits received a chow diet supplemented with a single conjugate of ursodeoxycholic acid ursodeoxycholyl-glycine, ursodeoxycholyl-sarcosine, ursodeoxycholyl-taurine or ursodeoxycholyl-N-methyltaurine for 3 wks at a dose of 50 mg/kg/day; a control group received chow alone. After 3 wks of feeding, animals receiving ursodeoxycholyl-glycine or ursodeoxycholyl-taurine had hepatotoxicity associated with abnormal liver tests. Lithocholic acid made up 11% +/- 2.7% of biliary bile acids in the ursodeoxycholyl-glycine and 10% +/- 2.2% in the ursodeoxycholyl-taurine group. In contrast, animals receiving ursodeoxycholyl-sarcosine or ursodeoxycholyl-N-methyltaurine had neither hepatotoxicity nor abnormal liver tests and the proportion of lithocholic acid in biliary bile acids increased much less. Complementary studies showed that ursodeoxycholyl-sarcosine and ursodeoxycholyl-N-methyltaurine were not biotransformed during hepatic transport and were resistant to deconjugation and dehydroxylation in the rabbit. These experiments indicate that the N-methyl amino acid conjugates of ursodeoxycholic acid are nontoxic in the rabbit and resist deconjugation and dehydroxylation. Such resistance decreases formation of lithocholic acid in the colon, thus reducing its accumulation and consequent induction of hepatotoxicity.

Topics: Amino Acids; Animals; Bile Acids and Salts; Bile Ducts; Biotransformation; Body Weight; Cholesterol; Deoxycholic Acid; Diet; Guinea Pigs; Liver; Male; Organ Size; Rabbits; Ursodeoxycholic Acid

The pharmacokinetics and toxicity of the lipophilic antifungal agent, amphotericin-B (AmpB), were studied in the hyperlipidemic obese rat model and compared with lean litter-mates. Serial blood samples were obtained for 36 h following a single intravenous infusion of AmpB (1.2 mg/kg) with pre- and post-drug measurements of renal function. Although triglyceride, cholesterol, HDL-cholesterol and LDL + VLDL-cholesterol levels were elevated in the obese compared with lean rats, protein: lipoprotein ratios were similar. There was a 2-fold increase in the area under the serum concentration-time curve of AmpB in obese rats compared to lean litter-mates (15,600 +/- 6900 v. 7800 +/- 2900 ng. h/ml; P less than 0.05); no differences in elimination rate constants were found between groups. Weight-corrected volume of distribution and total body clearance were significantly lower in obese compared with lean rats; no differences were found in absolute clearance or volume. Kidney levels of AmpB were markedly increased in obese versus lean rats. Similarly, kidney to serum ratios of AmpB were greater in obese compared with lean rats (152 +/- 113 v. 41 +/- 23; P less than 0.001). There was a significant decline in the creatinine clearance from baseline in the obese rats coupled with a rise in serum creatinine; no differences were found in lean rats. Similarities in absolute pharmacokinetic variables and protein: lipoprotein ratios suggest differences in AmpB disposition and toxicity are a result of differences in lipoprotein-mediated transport mechanisms between obese and lean rats.

Topics: Amphotericin B; Animals; Antifungal Agents; Body Weight; Deoxycholic Acid; Drug Combinations; Female; Kidney; Metabolic Clearance Rate; Obesity; Rats; Rats, Zucker

Ursodeoxycholic acid (ursodiol) has been shown to be an effective oral agent for dissolution of gallstones that also has a favorable safety profile. In the selection of patients as candidates for this treatment, stone characteristics and the functional status of the gallbladder are the two most important criteria. Small, primarily cholesterol stones (radiolucent on plain film) are the most suitable for oral dissolution therapy. In addition, a functioning gallbladder (as evidenced by visualization on oral cholecystogram) is required to concentrate the ursodiol-enriched bile and effect stone dissolution. Ursodiol should not be used during pregnancy, in women likely to become pregnant, or in severe acute or chronic intrahepatic cholestasis. Acute cholestasis and common bile duct obstruction also preclude this treatment. Screening tests include basic laboratory tests of liver function, sonographic evaluation of the gallbladder and biliary tree, plain film of the abdomen, and oral cholecystogram. Since few patients meet all the selection criteria ideally, the decision to undertake treatment with ursodiol must be based on the entire clinical profile and on the patient's willingness to accept the predicted likelihood of success.

Topics: Age Factors; Body Weight; Cholelithiasis; Cholesterol; Deoxycholic Acid; Gallbladder; Humans; Ursodeoxycholic Acid

Hamsters were fed chenodeoxycholic acid (CDC), ursodeoxycholic acid, (UDC), or no bile acid. [14C]Sucrose-labeled hamster low density lipoprotein (LDL) and methylated human LDL were infused intravenously to study LDL receptor-dependent and LDL receptor-independent organ uptake, respectively, of LDL. Biliary CDC increased during both CDC and UDC treatment. The UDC enrichment of bile after UDC feeding was relatively small. Bile acid synthesis was suppressed after both bile acid treatments. Under the condition of an acute bile fistula, the hamster LDL uptake increased in the liver, heart, and adrenals in the CDC-treated animals. During an intact enterohepatic circulation, the hepatic uptake of hamster LDL, which accounted for a major portion of the total uptake, was increased after UDC treatment. The hamster LDL uptake in the colon, which represented only a small fraction of the total uptake, increased after CDC treatment. When hamster LDL was infused at increasing concentrations, its uptake was significantly higher in the UDC-treated than in the control and CDC-treated animals. The methylated human LDL uptake showed no significant changes in the different treatment groups under either experimental condition. The study shows significantly different effects of CDC and UDC on LDL receptor activity. Since these differences are expressed in spite of a similar suppression of bile acid synthesis, UDC may directly influence LDL receptor activity.

Topics: Albumins; Animals; Bile Acids and Salts; Body Weight; Chenodeoxycholic Acid; Cricetinae; Deoxycholic Acid; Enterohepatic Circulation; Feces; Gallbladder; Lipoproteins, HDL; Lipoproteins, LDL; Liver; Male; Mesocricetus; Organ Size; Receptors, Cell Surface; Receptors, Lipoprotein; Ursodeoxycholic Acid

The aim of the present study was to evaluate whether treatment with ursodeoxycholic acid (UDCA) may affect the absorption of dietary fat in man. Fifteen healthy subjects volunteered for the study. They were treated with UDCA in a daily dose of 15 mg/kg body weight for 4 weeks. Before and during treatment fat absorption was measured with a 14C-triolein breath test. In addition, fasting serum bile acids were measured in 11 of the subjects. The maximum specific activity of 14CO2 was not significantly changed during the treatment period. However, the cumulative output of 14CO2 during a 6-h period was decreased by about 25% (p less than 0.03). Several subjects with decreased outputs also lost 1-2 kg of body weight during the study period. UDCA treatment raised the serum level of this bile acid from 0.18 +/- 0.11 mumol/l to 5.98 +/- 1.08 mumol/l. The concentrations of the other bile acids were not significantly changed. It is suggested that UDCA treatment may in some patients be associated with an impaired fat absorption. Whether this effect is of any clinical importance remains to be elucidated.

Topics: Adult; Bile Acids and Salts; Body Weight; Breath Tests; Deoxycholic Acid; Dietary Fats; Female; Humans; Intestinal Absorption; Lipids; Liver; Male; Triglycerides; Triolein; Ursodeoxycholic Acid

Because the composition of faeces modulates colorectal carcinogenesis, promotional effects of the secondary bile salt sodium deoxycholate (SDC) were compared with those of dilute homogenised faeces (12.5% w/v) or saline alone in rat colon isolated from the faecal stream as a Thiry-Vella fistula (TVF). Each fluid was used to irrigate a group of TVFs 3 times per week for 12 weeks. Other rats had TVF without irrigation or colonic transection and reanastomosis (sham TVF). Operations followed a 6-week course of azoxymethane injections. At sacrifice 15 weeks postoperatively crypt depth and tumour yield were reduced to the same extent in both the non-irrigated TVFs and the SDC-irrigated TVFs, when compared to shams. Irrigation with faeces and saline completely restored crypt depth and partly restored tumour yields to the levels in shams. Tumours were smaller in the SDC group than in the other 4 groups. While tumours developed mainly in the left colon of shams, there was significantly more even distribution in the TVFs. Exclusion of the colon from the faecal stream leads to mucosal hypoplasia and impaired carcinogenesis. Irrigation with faeces or saline partly reverses these changes. Deoxycholate has no such effect and clearly is not co-carcinogenic in this model.

Topics: Animals; Azoxymethane; Body Weight; Cocarcinogenesis; Colonic Neoplasms; Deoxycholic Acid; Feces; Intestinal Neoplasms; Intestines; Male; Rats; Rats, Inbred Strains; Therapeutic Irrigation

Bile flow and biliary bile acids were analyzed in arteriolipidosis-prone rats (ALR), the hypertensive model for lipidemic arterial lesions with reactive hypercholesterolemia and compared to those in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). Bile flow and bile acid secretion decreased in the order of WKY, SHR and ALR. When labelled cholesterol was given intraperitoneally, the biliary radioactivity secretion was significantly slow in ALR in comparison with that in WKY. The decay of radioactive cholesterol in serum after the injection was also delayed in ALR. Our data suggest that the abnormality in bile flow, biliary bile acid secretion and/or cholesterol turnover to bile acids may be pathogenically related to reactive hypercholesterolemia noted in the ALR.

Topics: Animals; Arteriosclerosis; Bile Acids and Salts; Body Weight; Cholesterol; Cholic Acids; Deoxycholic Acid; Hypertension; Lipidoses; Liver; Male; Rats; Rats, Inbred Strains; Triglycerides

Biliary lipid classes (bile acids, phospholipids, cholesterol) as well as individual biliary bile acids were measured in duodenal bile samples obtained before treatment from 284 white men and 264 white women participating in the National Cooperative Gallstone Study. The patients had radiolucent gallstones present in visualizing gallbladders. Calculated biliary cholesterol saturation was significantly higher in women (143 +/- 43, mean +/- SD, vs. 132 +/- 39 for men). Chenodeoxycholic acid was the major biliary bile acid in both sexes (40.0 +/- 9.9 in men; 38.8 +/- 9.3 in women, NS). Cholic acid was the second most common bile acid, constituting 32.9 +/- 8.8 in men and 31.8 +/- 8.9 in women (NS). When other demographic and clinical characteristics, including serum lipids, were related with biliary lipid composition, only percent ideal body weight correlated significantly. The partial correlation coefficient adjusted for percent ideal body weight indicated that the proportion of chenodeoxycholic acid correlated negatively with the mole fraction of cholesterol in bile in men, but not in women. Multiple regression analyses showed that bile saturation could not be predicted reliably from any clinical, chemical, or radiologic measurement in either sex. Published data for biliary lipid composition in individuals with biliary disease showed considerable overlap with the National Cooperative Gallstone Study data reported here, suggesting that cholesterol gallstone disease is not caused solely by increased biliary cholesterol saturation.

Topics: Adult; Aged; Bile; Bile Acids and Salts; Body Weight; Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Deoxycholic Acid; Female; Humans; Lipids; Male; Middle Aged; Phospholipids; Radiography; White People

The hepatotoxic effects of cholelitholytic bile acids, ursodeoxycholic and chenodeoxycholic acids, were compared with each other and with those of lithocholic acid, a known hepatotoxic bile acid, in the rabbit. Male New Zealand white rabbits were fed regular laboratory chow containing ursodeoxycholic, chenodeoxycholic, or lithocholic acid at a concentration of 0.5 per cent (w/w) for 14 days. The control group was fed the chow without added bile acids. The mortality rate was highest (six of 12) in the lithocholate group, intermediate (two of eight) in the chenodeoxycholate group, and lowest (none of six) in the ursodeoxycholate group. Light microscopy of the liver revealed fibrosis, inflammation, and bile duct proliferation in the portal regions in the three experimental groups; however, the lesions in the lithocholate and chenodeoxycholate groups were more severe and often associated with periportal extension of fibrosis and focal necrosis of the parenchyma. In addition, electron microscopy revealed distortion of bile canaliculi, conspicuous bundles of intermediate-sized filaments, expansion of pericanalicular cytoplasmic matrix due to apparent accumulation of microfilaments, prominence of lysosomes, and fragmentation of cisternae of the rough endoplasmic reticulum. These ultrastructural changes were less marked and often absent in the ursodeoxycholate group. The serum L-alanine aminotransferase activity increased 5- to 6-fold in the lithocholate and chenodeoxycholate groups, whereas it remained less than 2-fold of the control level in the ursodeoxycholate group on day 14. The serum lithocholate concentration was markedly elevated to comparable levels in all three groups, whereas ursodeoxycholate was highly increased in the ursodeoxycholate group but undetectable in the other groups at the time of sacrifice. It is concluded that (1) although the oral administration of three bile acids induces hepatic injuries in the rabbit, ursodeoxycholate causes less severe injury than do the other two, (2) the advantage of ursodeoxycholate versus chenodeoxycholate is probably relative rather than absolute, (3) lithocholate formed through metabolic conversion from ursodeoxycholate may be responsible for the most part for hepatotoxicity, and (4) it is possible that the concurrent presence of ursodeoxycholate may mitigate lithocholate's hepatotoxicity.

Topics: Animals; Bile Canaliculi; Body Weight; Chemical and Drug Induced Liver Injury; Chenodeoxycholic Acid; Cytoskeleton; Deoxycholic Acid; Lithocholic Acid; Liver; Liver Diseases; Prognosis; Rabbits; Ursodeoxycholic Acid

Gastrointestinal disorders often occur during systemic chemotherapy. In an attempt to prevent these side-effects, ursodeoxycholic acid was administered during the systemic chemotherapy. This compound significantly alleviated the side-effects, as assessed by an increase in appetite, total serum protein level and body weight. However, in patients with a deficiency in pancreatic exocrine secretion and/or obstructive jaundice due to metastasis to common bile duct, the effects were nil.

Topics: Anorexia; Antineoplastic Agents; Blood Proteins; Body Weight; Deoxycholic Acid; Gastrointestinal Diseases; Humans; Ursodeoxycholic Acid

Topics: Amylases; Animals; Aspirin; Body Weight; Deoxycholic Acid; Dietary Fats; Female; Indomethacin; Pancreatitis; Rats; Sodium Chloride

The effect of coprophagy on the 7 alpha-dehydroxylation of biliary bile acids was studied in the rabbit. Bile acid composition of bile and intestinal contents was analyzed by gas-liquid chromatography and thin layer chromatography. Biliary bile acid composition of normal rabbits (n = 5) was: deoxycholic acid, 95.3 +/- 1.0SE % and cholic acid, 2.3 +/- 1.1SE %. When coprophagy was prevented, significant alterations were observed in biliary bile acid composition, including a considerable decrease in deoxycholic acid (82.5 +/- 2.8SE %, p less than 0.01) and a marked increase in cholic acid (15.2 +/- 3.0SE %, p less than 0.002). These results indicate that coprophagy is a factor causing an increase of the 7 alpha-dehydroxylated bile acid, deoxycholic acid (and lithocholic acid when the animals were fed chenodeoxycholic acid) in rabbit bile.

Topics: Animals; Bile Acids and Salts; Body Weight; Cecum; Chenodeoxycholic Acid; Cholic Acids; Coprophagia; Deoxycholic Acid; Eating; Humans; Lithocholic Acid; Male; Rabbits

Combined gas-liquid chromatography-mass spectrometry with specific ion monitoring (mass fragmentography) has been used for assay of cholic acic (C), chenodeoxycholic acid (CD), and deoxycholic acid (D) in human serum. Deuterium-labeled C and D were used as internal standards. The relative standard deviation of duplicate samples was 3, 4, and 7% for C, CD, and D, respectively. The variation within the same individual in the fasting state was small, while the day-to-day variation was greater, especially for the dihydroxy bile acids. In normal control subjects (n = 24), the fasting serum concentration of C averaged 184 +/- 24 ng/ml (mean +/- SEM), and that of CD and D 526 +/- 62 and 407 +/- 44 ng/ml, respectively. Patients with type IIa hyperlipoproteinemia (n = 32) displayed low values of serum bile acids, with a C concentration of 121 +/- 11 ng/ml (P less than 0.01 vs. controls). A similar pattern was seen in patients with a type IIb lipoprotein pattern (n = 10). Subjects with type IV hyperlipoproteinemia (n = 32) showed serum bile acid levels within the normal limits. No relationship to age, sex, or body weight was seen in any of the patient subgroups. Bile acid kinetics were determined with an isotope dilution technique using 14C-labeled C and CD under steady state conditions in control subjects and patients with type IIa and type IV hyperlipoproteinemia. The serum concentration of C correlated significantly to its pool size in control subjects and in patients with type IIa hyperlipoproteinemia but not in patients with type IV. The serum level of CD was not related to CD pool size in any of the subgroups. The data obtained are discussed in relation to present concepts of the enterohepatic circulation. It is suggested that the intestinal content of C in the fasting state is proportional to the total C pool size. The possibility of a defective intestinal uptake of C in some patients with type IV hyperlipoproteinemia is raised.

Topics: Bile Acids and Salts; Body Weight; Chenodeoxycholic Acid; Cholic Acids; Deoxycholic Acid; Female; Gas Chromatography-Mass Spectrometry; Humans; Hyperlipidemias; Male; Middle Aged

In view of the excess prevalence of gallstones among women and the association of gallstones with diminished bile acid pool size, we measured bile acid pools in 27 male and 25 female healthy human volunteers. The average bile acid pool in the women was significantly smaller than in the men (2.25 +/- .12 g versus 2.88 +/- .16 g; p = 0.003). Chenodeoxycholic acid pool size, computed from bile acid composition data available in 43 of these subjects, was also smaller in women than men (0.94 +/- 0.06 versus 1.22 +/- 0.07 g; p = 0.004). Age, race, and body size bore no statistically significant relationship to bile acid pool size. Biliary cholesterol saturation was positively correlated with weight and obesity and showed a significant inverse correlation with chenodeoxycholic acid pool size, but not with total bile acid pool size. These findings suggest a possible mechanism for the higher prevalence of gallstones among women.

Topics: Adolescent; Adult; Arizona; Bile Acids and Salts; Body Height; Body Weight; Chenodeoxycholic Acid; Cholelithiasis; Cholic Acids; Deoxycholic Acid; Female; Humans; Indians, North American; Male; Sex Factors; White People

An assay using radioactive substrates is described that permits rapid determinations of glycerophospholipid-hydrolyzing activity in postheparin plasma or its fractions. Optimal conditions are described for hydrolysis of phosphatidylcholine and phosphatidylethanolamine. A minimum of only 2 mul of normal postheparin plasma is used and no extraction of the reaction products is required before their separation by thin-layer chromatography. We found that after an optimal heparin dose of 60 units/kg body weight the rate of hydrolysis for diacyl glycerophosphocholine and diacyl glycerophosphoethanolamine is 1.16 mumoles/ml per hr and 22.4 mumoles/ml per hr, respectively.

Topics: Body Weight; Carboxylic Ester Hydrolases; Deoxycholic Acid; Esterases; Heparin; Humans; Hydrogen-Ion Concentration; Kinetics; Male; Methods; Phospholipids; Temperature

Inhibition by saccharin of rat liver glucose-6-phosphatase (EC 3.1.3.9) generally decreased as the pH increased in the range pH 4-8. This pattern was exhibited by homogenates from control and alloxan-treated animals assayed each in the absence and presence of 0.2% (w/v) deoxycholate. Saccharin inhibited in competitive fashion with respect to glucose-6-phosphate (glucose-6-P). There was a small increase in Km (glucose-6-P) but not K1 (saccharin) values in alloxan-treated rats when assays were conducted in the absence of deoxycholate. In the presence of this detergent there was no significant difference in these kinetic parameters between the alloxan-treated and control groups. Deoxycholate decreased Km (glucose-6-P) and increased K1 (saccharin) values. Calculations using these kinetic parameters indicate that, under usual hepatic glucose-6-P concentrations and relatively high levels of saccharin in liver, the inhibition by saccharin of glucose-6-phosphatase is unlikely to be of major significance in vivo.

Topics: Alloxan; Animals; Binding, Competitive; Blood Glucose; Body Weight; Deoxycholic Acid; Diabetes Mellitus, Experimental; Glucose-6-Phosphatase; Kinetics; Liver; Male; Organ Size; Rats; Saccharin

Chenodeoxycholic acid is an important drug for the treatment of cholesterol cholelithiasis in man. Although no toxicity has been demostrated in man, liver lesions develop in rhesus monkeys treated with chenodeoxycholic acid. To elucidate the mechanism of toxicity, chenodeoxycholic acid. To elucidate the mechanism of toxicity, chenodeoxycholic acid was fed daily to three groups of 6 animals each at the following dose: 10, 40, and 100 mg per kg; 2 separate animals were not treated and served as controls. After 1 month, the animals were killed. During the treatment period, most blood tests (e.g., blood count, blood urea nitrogen, albumin, SGOT, lactate dehydrogenase) remained within normal limits, but there was a significant dose-related increase in serum leucine aminopeptidase levels. The percentage of lithochlic acid, the 7-dehydroxylated bacterial metabolite of chenodeoxycholic acid, rose from 1% in the control animal to almost 14% in the 100 mg per kg-treated group. Liver biopsies obtained before treatment and at necropsy showed no significant changes. Thus, exposure of the liver to increased amounts of lithocholic acid during chenodeoxycholic acid treatment might result in elevation of serum leucine aminopeptidase activity.

Topics: Animals; Bile; Body Weight; Chenodeoxycholic Acid; Cholelithiasis; Cholesterol; Cholic Acids; Deoxycholic Acid; Diarrhea; Dose-Response Relationship, Drug; Female; Leucyl Aminopeptidase; Lithocholic Acid; Liver; Macaca mulatta; Male; Phospholipids

Topics: Animals; Appetite; Bile; Bile Acids and Salts; Body Weight; Chemical and Drug Induced Liver Injury; Chenodeoxycholic Acid; Cholesterol; Cholic Acids; Deoxycholic Acid; Diet; Lithocholic Acid; Liver; Liver Cirrhosis; Male; Rabbits

Topics: Animals; Body Weight; Carbon Radioisotopes; Chromatography, Gas; Chromatography, Thin Layer; Deoxycholic Acid; Female; In Vitro Techniques; Liver; Male; Organ Size; Perfusion; Rats; Sex Factors

Topics: Animals; Bile Acids and Salts; Body Weight; Carbon Radioisotopes; Carcinogens; Cholesterol; Cholic Acids; Colonic Neoplasms; Deoxycholic Acid; Dietary Fats; Feces; Hydrazines; Lithocholic Acid; Male; Rats; Sterols

Topics: Age Factors; Animals; Body Weight; Deoxycholic Acid; Dietary Proteins; DNA; Female; Lactation; Liver; Maternal-Fetal Exchange; Nutrition Disorders; Organ Size; Polyribosomes; Pregnancy; Pregnancy Complications; Protein-Energy Malnutrition; Proteins; Rats; Ribosomes; RNA; Sodium

Topics: Administration, Oral; Animal Feed; Animals; Bile Acids and Salts; Body Weight; Cholelithiasis; Cholesterol; Cholic Acids; Cricetinae; Deoxycholic Acid; Disease Models, Animal; Fatty Acids; Female; Lithocholic Acid; Liver; Male; Organ Size; Sex Factors; Testis

Killed vaccines, deoxycholate-extracted or heated, were shown to induce an effective degree of immunity which protected against death (100%), prevented extensive multiplication, and left the mice with low residual salmonella populations in spleen and liver after intravenous (iv) or intraperitoneal (ip) challenge with virulent Salmonella typhimurium. Protection was most effective against the ip challenge route and less effective against the iv route. A study of the kinetics of the population of bacteria in the spleens and livers of immunized animals showed that after ip challenge there was an initial reduction of 99% at 6 hr after challenge, maintenance of levels of less than 10(3) bacteria per organ, and a final population of 10(2) to 10(3) per organ at 21 days. With iv challenge, after an initial reduction of 90% at 6 hr, growth ensued to levels above 10(6) bacteria per organ until 8 days, followed by a steady decline yielding residual populations of 10(3) to 10(4) in some cases. Organ hypertrophy correlated with bacterial population. Morbidity was prevented (as measured by gain in body weight) by immunization against ip challenge but not against iv challenge. Killed vaccines protected by their ability to induce an immune state which reduced the initial challenge population, prevented extensive multiplication, yet allowed "cellular immunity" to develop due to response to the living challenge infection itself. The consequence was a low-level carrier state similar to that induced by recovery from sublethal virulent infection.

Topics: Animals; Bacterial Vaccines; Body Weight; Deoxycholic Acid; Female; Hypertrophy; Immunity, Cellular; Immunization; Injections, Intraperitoneal; Injections, Intravenous; Kinetics; Lethal Dose 50; Liver; Mice; Organ Size; Salmonella Infections; Salmonella typhimurium; Spleen; Time Factors