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PubMed1977

Lack of toxicity of chenodeoxycholic acid in the squirrel monkey.

The toxicity of chenodeoxycholic acid was studied in squirrel monkeys of both sexes. The drug was orally administered to five groups of 26 animals each at a daily dose of 0, 10, 20, 40, and 80 mg per kg, respectively, for a maximum of 52 weeks. No clinical symptoms that could suggest drug toxicity were observed. All laboratory studies, including liver function tests, were within normal limits. The proportion of lithocholic acid in biliary acids remained unchanged, whereas that of chenodeoxycholic acid was dose-dependently increased. No histopathological changes considered to be attributable to drug administration were observed.

Administration, Oral↗
PubMed1975

Treatment of gallstones with chenodeoxycholic acid and phenobarbital.

In a controlled trial, 36 patients with asymptomatic radiolucent gallstones were treated with chenodeoxycholic acid, 750 mg per day, phenobarbital, 180 mg per day, combination of both drugs, and placebo. After one year, chenodeoxycholic acid, phenobarbital and the combination, but not placebo, significantly decreased biliary cholesterol saturation. The effect was significantly greater with chenodeoxycholic acid and the combination than with phenobarbital. Gallstones size decreased more than 50 per cent in nine of 20 patients receiving chenodeoxycholic acid, either alone or combined with phenobarbital, but in no patient receiving only phenobarbital or placebo. Gallstones disappeared completely in tow patients. Abnormalities in liver-function tests in thriee of 36 patients and in five of 16 liver biopsies, occured with equal frequency in the four treatment groups. Thus, after one year, phenobarbital alone was ineffective in gallstone dissolution. Chenodeoxycholic acid alone or combined with phenobarbital, however, offered a partially effective and safe treatment for asymptomatic radiolucent gallstones.

Adult↗
PubMed1978

Diurnal serum levels of primary conjugated bile acids. Assessment by specific radioimmunoassays for conjugates of cholic and chenodeoxycholic acid.

The serum levels of conjugates of chenodeoxycholic acid (chenyl conjugates) and of cholic acid (cholyl conjugates) were determined by specific radioimmunoassays during a 24-hour period, which included three liquid meals and an overnight fast, in five healthy volunteers, five patients with previous cholecystectomy, five patients with documented bile acid malabsorption because of ileal resection, and four pregnant women. In healthy subjects, fasting-state levels of chenyl conjugates, when compared with those of cholyl conjugates, were higher; postprandially, levels of chenyl conjugates rose to a peak sooner (30 minutes vs 60 minutes) and to higher levels (5.2 +/- 1.3 muM vs 2.0 +/- 0.5 muM, M +/- SE). In cholecystectomised patients, the integrated areas under the curve for both bile acids were similar to those of the healthy controls, but postprandial peaks were less marked. In patients with bile acid malabsorption, postprandial rises of chenyl conjugates were lower but remained relatively constant throughout the day, whereas cholyl conjugate levels diminished progressively with each successive meal, consistant with depletion of the cholyl, but not the chenyl, pool. In three of four pregnant women, the postprandial rise of chenyl conjugates was disproportionately less compared with that of healthy controls. These results confirm the dynamic complexity of serum bile acid levels in man and indicate that the major circulating primary bile acids are chenyl conjugates. They support previous proposals that jejunal absorption of chenyl conjugates is important in the normal enterohepatic circulation of bile acids; and they suggest an abnormality in the enterohepatic circulation in pregnancy.

Chenodeoxycholic Acid↗
PubMed1976

Semiquantitative measurement of lithocholic acid compounds in bile from patients with gallstones, before and during treatment with chenodeoxycholic acid.

A method for two-dimensional thin-layer chromatography of unprocessed bile is described. The method gives distinct spots from lithocholic acid and its compounds with glycine, taurine, and sulfuric acid. The size of the spots is estimated by comparison with standard spots, and the concentrations of individual bile acids are expressed as a fraction of the total content of bile acids in the sample. The concentration of total lithocholic acid was found to be 1-3 (mean 1.5) per cent of the total concentration of bile acids in duodenal bile from 14 healthy persons. It was slightly higher in bile from 6 untreated patients with gallstones, and still higher, 3-7 (mean 4.0) per cent, in bile from the same patients during treatment with chenodeoxycholic acid. The difference between the concentrations of total lithocholic acid in the bile samples from healthy persons and from patients treated with chenodeoxycholic acid was statistically significant. Nearly all the lithocholic acid was conjugated with glycine or taurine, and approximately half of it was sulfated. The increase in total lithocholic acid concentration in the bile from patients consisted of glycine conjugates.

Bile↗
PubMed1976

Metabolism of chenodeoxycholic acid in hamsters.

The study on the metabolism after oral administration of chenodeoxycholic acid-24-14C was performed by analysis of radioactivity that had appeared in bile and feces of male hamsters. The radioactive bile acids were analyzed by thin layer chromatography and identified by the isotope dilution method. In the bile of the hamsters with bile fistula, radioactivity was originated from unchanged chenodeoxycholic acid for the most part, and 7-ketolithocholic acid, lithocholic acid, and beta-muricholic acid for the remainder. In the feces lithocholic acid, dehydrolithocholic acid, isolithocholic acid, and unchanged form were identified. After the multiple dosing of chenodeoxycholic acid-24-14C for 6 days, beta-muricholic acid was also identified in the feces.

Administration, Oral↗
PubMed1977

Dietary cholesterol affects chenodeoxycholic acid action on biliary lipids.

Chenodeoxycholic acid (CDC) decreases biliary saturation and dissolves gallstones in one-half of the treated patients. Dietary cholesterol also affects biliary lipids and is a possible factor explaining unsuccessful CDC therapy. The aim of this investigation was to study the effect of high and low dietary cholesterol on the CDC-induced decrease of biliary saturation and activity of hepatic hydroxymethylglutaryl coenzyme A reductase (HMG-CoAR). Seventy two hamsters in six groups were fed for 1 month one of three diets: 0.8 mg of cholesterol per g of food, 2.4 mg of cholesterol per g, or cholesterol-free. On each diet hamsters received no CDC or CDC 30 mg per kg per day. When animals were killed, biliary lipids were determined and the activity of hepatic HMG-CoAR was assayed. CDC administration decreased the saturation index (SI)(P less than 0.01) in hamsters on the high cholesterol and standard diets but not on the cholesterol-free diet. The SI in CDC-treated hamsters on the high cholesterol (0.78 +/- 0.03) and cholesterol-free (0.68 +/- 0.02) diets were greater (P less than 0.02) than in CDC-treated hamsters on the standard diet (0.48 +/- 0.03). CDC decreased (P less than 0.01) HMG-CoA reductase activity on each diet. In comparison to HMG-CoAR activity (190 +/- 7.6 pmoles per mg per min) in CDC-treated hamsters on the standard diet, the activity in CDC-treated hamsters on the high cholesterol diet (176 +/- 5.8 pmoles per mg per min) was decreased ( less than 0.05), whereas the activity on the cholesterol-free diet (495 +/- 11.5 pmoles per mg per min) was greater (P less than 0.01). It is concluded that: (1) dietary cholesterol is necessary for optimum CDC inhibition of HMG-CoAR; (2) high cholesterol and cholesterol-free diets prevent maximum CDC decrease of the biliary saturation index; (3) dietary cholesterol alterations may therefore be one cause of the failure of CDC dissolution of gallstones.

Animals↗
PubMed1973

Effect of oral chenodeoxycholic acid on bile acid kinetics and biliary lipid composition in women with cholelithiasis.

Bile acid kinetics and biliary lipid composition were characterized in six women with gallstones before and after 6 mo of oral therapy with chenodeoxycholic acid, an agent that induces dissolution of cholesterol gallstones in man. Over a dosage range of 1-4 g/day, absorption varied from 0.8 to 2.3 g/day. The chenodeoxycholic acid pool expanded two-to sixfold, and bile became composed predominantly (> 90%) of chenodeoxycholic acid conjugated chiefly with glycine. Cholic acid and deoxycholic acid pools decreased markedly, so that the total bile acid pool expanded much less, about twofold on the average. Cholic acid synthesis decreased in five of the six patients, consistent with negative feedback inhibition of cholic acid synthesis by chenodeoxycholic acid. In four patients whose bile was above or close to saturation with cholesterol, the bile became unsaturated; in two patients, whose bile was unsaturated, it remained so. In five patients with radiolucent gallstones, chenodeoxycholic acid therapy was continued after completion of kinetic and composition measurements; the stones decreased in size or dissolved entirely during the subsequent 6 to 18 mo. Similar measurements of bile acid kinetics and biliary lipid composition were made before and after a 6-mo period without medication in a control group of six healthy women; no changes occurred.

Administration, Oral↗
PubMed1984

Analysis of metabolic profiles of steroids in faeces of healthy subjects undergoing chenodeoxycholic acid treatment by liquid-gel chromatography and gas-liquid chromatography-mass spectrometry.

The multicomponent analysis of faecal steroids is described. Steroids were removed from faeces by solvent stripping in a Soxhlet apparatus and the resulting extracts were fractionated by diethylaminohydroxypropyl Sephadex column chromatography into neutral sterols, free bile acids, glycine conjugated bile acids, taurine conjugated bile acids and sulphated steroids. In this study the method has been applied for faecal steroid analyses of healthy subjects undergoing chenodeoxycholic acid therapy. Chenodeoxycholic acid administration causes a considerable increase in the concentration of faecal lithocholic acid which is a known comutagenic bile acid. Furthermore it has been shown that conjugated bile acids can account for between 10 and 20% of the faecal bile acid pool. The method described is convenient and may be useful for epidemiological studies which require a large number of faecal samples to be analysed.

Bile Acids and Salts↗
PubMed1985

Conjugation, metabolism and excretion of [24-14C] chenodeoxycholic acid in patients with extrahepatic cholestasis before and after biliary drainage-analysis of conjugated bile acids by HPLC.

[24-14C] chenodeoxycholic acid (CDC) was given to patients with total extrahepatic cholestasis two or three days before an external drainage was made, and excretion of the isotope in urine and bile followed. Bile acids were group-separated by anion exchange chromatography on DEAP-Sephadex LH-20 and the individual conjugates isolated by HPLC. 51.0-75.4% of the administered isotope was excreted; 16.2-29.9% as sulphates, 0.1-2.4% as glucuronides and 20.7-58.7% as glycine and taurine conjugates. 5.2-21.0% of excreted isotope consisted of transformation products of CDC, mainly cholic acid, hyocholic acid and ursodeoxycholic acid. Labelled urinary sulphates were the 3-sulphates of glycochenodeoxycholic and taurochenodeoxycholic acid. During cholestasis the renal clearance was about ten times higher for the sulphates compared with the non-sulphated conjugate. The clearance of glycine conjugates and their sulphates was of the same magnitude as that of the corresponding taurine conjugates. During the biliary drainage period, most of the labelled sulphates were excreted in urine, while most of the glycine and taurine conjugates were excreted in bile.

Aged↗
PubMed1994

Breast-gut connection: origin of chenodeoxycholic acid in breast cyst fluid.

The notion that a breast-gut connection might modulate the microenvironment of breast tissue was supported by the finding that breast cyst fluid contains bile acids that are characteristically found in the intestines. To establish that the gut, rather than circulating steroid precursors, is the source of bile acids in breast cyst fluid, we gave two patients deuterium-labelled chenodeoxycholic acid (three 200 mg doses by mouth), starting 9 days before aspiration of breast cysts. The chenodeoxycholic acid concentration of seven samples of aspirated cyst fluid ranged from 42 to 94 mumol/L. The corresponding serum concentrations of chenodeoxycholic acid on the same day were 0.8 and 2.9 mumol/L, of which the labelled compound comprised 13.0% (0.38 mumol/L) and 28.2% (0.23 mumol/L). The deuterated chenodeoxycholic acid concentrations in cyst fluid were 0.79 and 1.26 mumol/L in two samples from patient 1 and 3.22 mumol/L in patient 2; these values are equivalent to 11-17% of the serum concentrations [corrected]. This study shows that intestinal bile acids rapidly gain access to cyst fluid. Further studies should investigate the mechanisms that govern the exchange processes and the maintenance of the high cyst fluid to plasma concentration gradients, and the biological half-lives of individual constituents.

Adult↗
PubMed1991

Distribution of cholesterol between vesicles and micelles in human gallbladder bile: influence of treatment with chenodeoxycholic acid and ursodeoxycholic acid.

The present study aimed at determining the relative distribution of cholesterol between the vesicular and micellar phases in gallbladder bile of gallstone patients (n = 23) and gallstone-free subjects (n = 7). Nine of the gallstone patients were treated with chenodeoxycholic acid and seven were treated with ursodeoxycholic acid, 15 mg/kg/day, for 3 wk before cholecystectomy. The vesicular and micellar fractions in bile were separated by sucrose density gradient ultracentrifugation, and a clear separation between the two phases was obtained. The vesicles were further identified by quasielastic light scattering spectroscopy and appeared to be of a uniform size with a mean hydrodynamic radius of 760 A. The proportion of cholesterol in the vesicular fraction was significantly higher in the untreated gallstone group (40% +/- 4%) compared with the gallstone-free (28% +/- 3%), ursodeoxycholic acid (28% +/- 3%) and chenodeoxycholic acid (18% +/- 4%) groups. Despite a low cholesterol saturation of bile in the latter three groups (88% +/- 12%, 51% +/- 9% and 65% +/- 5%, respectively), a considerable part of the biliary cholesterol was carried in the vesicular fraction. The cholesterol/phospholipid ratio in the vesicular fraction averaged between 0.49 and 0.58 in the gallstone, gallstone-free and chenodeoxycholic acid groups, whereas the ursodeoxycholic acid group had a significantly lower ratio of 0.24. The nucleation time of bile from the gallstone group was short (2 +/- 1 days) compared with the gallstone-free, chenodeoxycholic acid and ursodeoxycholic acid groups (23 +/- 3, 24 +/- 6 and 14 +/- 3 days, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1985

Effect of chenodeoxycholic acid on biliary and urinary bile acids and bile alcohols in cerebrotendinous xanthomatosis; monitoring by high performance liquid chromatography.

Biliary and urinary bile alcohol and bile acid composition has been determined by high performance liquid chromatography in patients with cerebrotendinous xanthomatosis before and after treatment with chenodeoxycholic acid. Most of the bile acids and bile alcohols in the bile and urine were separated in less than 30 min using a radial pack C18 muBondapak 5 micron particle size column with a mobile phase of acetonitrile-water-methanol-acetic acid 70:70:20:1 (v/v/v/v) at a flow rate of 2 ml/min, and a refractive index detector. Before treatment, cholic acid (49%) and 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 25-tetrol (27%) were the major biliary bile acid and bile alcohol, respectively, but were not detected in the urine of five patients. 5 beta-Cholestane-pentols were, instead, the major urinary bile alcohols with 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 23 xi, 25-pentol (56%) predominating. Whereas 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 24S,25-pentol was not detected in the bile, it was isolated in the urine of all patients (27%). The only urinary bile acid isolated by high performance liquid chromatography was nor-cholic acid. After 1 month of treatment with chenodeoxycholic acid, 0.75 g/day, chenodeoxycholic acid became the major bile acid in the bile of all patients (71%) along with its metabolite, ursodeoxycholic acid (21%). Cholic acid and 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 25-tetrol were drastically reduced and were only 3% each. The excretion of 5 beta-cholestane-pentols in the urine was also drastically reduced from 130 mg/day to 15 mg/day.

Bile↗
PubMed1977

[Treatment of patients with gallstones with chenodeoxycholic acid (author's transl)].

24 patients with cholesterol gallstones were treated with chenodeoxycholic acid. In 7 out of 10 patients the follow-up showed complete dissolution of the gallstones after 7 to 18 months of treatment with 1 g of chenodeoxycholic acid daily. Two patients with biliary duct concrements had to be operated, in a third patient no change could be observed after treatment for 17 months. A transient increase of the transaminase GOT was seen in four patients. There were no changes of serum cholesterol and triglyceride levels. 14 patients had chologenic diarrhoea lasting only a few days. Toxic side effects indisputably due to chenodeoxycholic acid therapy have not been seen so far.

Adult↗
PubMed1974

Liver structure and function in cholelithiasis: effect of chenodeoxycholic acid.

Although, in suitable patients, oral chenodeoxycholic acid (CDCA) dissolves gallstones, the results of recent animal studies suggest that it might be hepatotoxic. Liver function was therefore studied in patients with gallstones before and during treatment with CDCA and liver biopsies were carried out both in patients with cholelithiasis given bile acid therapy and in those who had been given no medical treatment. In 25 patients treated with 0.5-1.5 g CDCA/day (7-20 mg kg body weight(-1) day(-1)) there was no significant change in serum bilirubin, albumin, globulin, transaminase, isocitric dehydrogenase, alkaline phosphatase, and gamma glutamyl transpeptidase levels before and at monthly intervals during six months' treatment. The kinetics of bromsulphthalein (BSP) clearance and its apparent transport maximum were not significantly changed during CDCA therapy. The mean fasting serum bile acid concentrations of 18.0 +/- SEM 1.2 mumoles/litre before and 20.0 +/- 3.5 mumoles/litre during treatment were both significantly greater than control values. Liver histology was not appreciably different in 11 patients treated with CDCA from that in eight patients with untreated cholelithiasis and in three patients who had received CDCA three to four months before biopsy. These results suggest that in doses of 0.5 to 1.5 g/day CDCA is not hepatotoxic in man.

Adult↗
PubMed2005

Protective effects of 6-ethyl chenodeoxycholic acid, a farnesoid X receptor ligand, in estrogen-induced cholestasis.

The farnesoid X receptor (FXR), an endogenous sensor for bile acids, regulates a program of genes involved in bile acid biosynthesis, conjugation, and transport. Cholestatic liver diseases are a group of immunologically and genetically mediated disorders in which accumulation of endogenous bile acids plays a role in the disease progression and symptoms. Here, we describe the effect of 6-ethyl chenodeoxycholic acid (6-ECDCA or INT-747), a semisynthetic bile acid derivative and potent FXR ligand, in a model of cholestasis induced by 5-day administration of 17alpha-ethynylestradiol (E(2)17alpha) to rats. The exposure of rat hepatocytes to 1 microM 6-ECDCA caused a 3- to 5-fold induction of small heterodimer partner (Shp) and bile salt export pump (bsep) mRNA and 70 to 80% reduction of cholesterol 7alpha-hydroxylase (cyp7a1), oxysterol 12beta-hydroxylase (cyp8b1), and Na(+)/taurocholate cotransporting peptide (ntcp). In vivo administration of 6-ECDCA protects against cholestasis induced by E(2)17alpha. Thus, 6-ECDCA reverted bile flow impairment induced by E(2)17alpha, reduced secretion of cholic acid and deoxycholic acid, but increased muricholic acid and chenodeoxycholic acid secretion. In vivo administration of 6-ECDCA increased liver expression of Shp, bsep, multidrug resistance-associated protein-2, and multidrug resistance protein-2, whereas it reduced cyp7a1 and cyp8b1 and ntcp mRNA. These changes were reproduced by GW4064, a synthetic FXR ligand. In conclusion, by demonstrating that 6-ECDCA protects against E(2)17alpha cholestasis, our data support the notion that development of potent FXR ligands might represent a new approach for the treatment of cholestatic disorders.

Animals↗
PubMed1984

Chenodeoxycholic acid pool size determination from children using isotope dilution mass spectrometry.

An isotope dilution mass spectrometry method is described for determining chenodeoxycholic acid pool size in children. The stable isotopically labeled tracer, (11,12-2H2) chenodeoxycholic acid, was administered orally to children, and the enrichment of bile was measured by selected ion monitoring gas chromatography mass spectrometry. The level of (11,12-2H2)chenodeoxycholic acid enrichment found in the patient samples was in the range of 0.5 to 5%. Data are presented illustrating the duplication of this method in two independent laboratories using standard quadrupole mass spectrometers. This procedure provides the clinician with a non-radioactive method for determining chenodeoxycholic acid pool size which is especially beneficial in studies involving children and pregnant women.

Chenodeoxycholic Acid↗
PubMed1988

Determination of individual serum bile acids in chronic liver diseases: fasting levels and results of oral chenodeoxycholic acid tolerance test.

Fifteen bile acids in serum of 5 normal subjects and 21 patients with chronic liver diseases were fractionated by high performance liquid chromatography. Fasting total bile acids (TBA), glycocholic acid, taurocholic acid, glycochenodeoxycholic acid (GCDCA), and taurochenodeoxycholic acid (TCDCA) were significantly increased in patients with liver cirrhosis as compared with normal subjects. The cholic acid (CA) level and the ratio of the sum of free and conjugated CA to the sum of free and conjugated chenodeoxycholic acid (CDCA) were significantly elevated in patients with compensated as compared with decompensated liver cirrhosis, and were useful for differentiation of the two conditions. Serum bile acid levels were determined after oral administration of 500 mg of CDCA in the 5 normal subjects and 11 patients with liver disease. The TBA level reached a peak 90 min after CDCA administration in patients with chronic hepatitis and after 120 min in those with liver cirrhosis. The increase in the TBA level was significantly greater in patients with liver disease than in normal subjects. CDCA, GCDCA, and TCDCA showed changes similar to those in TBA. In patients with decompensated liver cirrhosis, the reduction in the TBA and CDCA levels after the peaks was slow, and GCDCA and TCDCA levels continued to increase until 180 min after the administration of CDCA. The TBA and CDCA levels 180 min after CDCA administration were significantly different among normal subjects, patients with chronic hepatitis, those with compensated liver cirrhosis, and those with decompensated liver cirrhosis, suggesting the usefulness of CDCA administration in differentiation of these conditions.

Bile Acids and Salts↗