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Biomedical subjects

A F Hofmann

Publications and source records attributed to A F Hofmann.

At least 55 records · Page 3Linked to original sources
PubMed1997

Successful topical dissolution of cholesterol gallbladder stones using ethyl propionate.

Topical dissolution of cholesterol gallbladder stones using methyl tert-butyl ether (MTBE) is useful in symptomatic patients judged too ill for surgery. Previous studies showed that ethyl propionate (EP), a C5 ester, dissolves cholesterol gallstones rapidly in vitro, but differs from MTBE in being eliminated so rapidly by the liver that blood levels remain undetectable. Our aim was to test EP as a topical dissolution agent for cholesterol gallbladder stones. Five high-risk patients underwent topical dissolution of gallbladder stones by EP. In three patients, the solvent was instilled via a cholecystostomy tube placed previously to treat acute cholecystitis; in two patients, a percutaneous transhepatic catheter was placed in the gallbladder electively. Gallstone dissolution was assessed by chromatography, by gravimetry, and by catheter cholecystography. Total dissolution of gallstones was obtained in four patients after 6-10 hr of lavage; in the fifth patient, partial gallstone dissolution facilitated basketing of the stones. In two patients, cholesterol dissolution was measured and averaged 30 mg/min. Side effects were limited to one episode of transient hypotension and pain at the infusion site; no patient developed somnolence or nausea. Gallstone elimination was associated with relief of symptoms. EP is an acceptable alternative to MTBE for topical dissolution of cholesterol gallbladder stones in high-risk patients. The lower volatility and rapid hepatic extraction of EP suggest that it may be preferable to MTBE in this investigational procedure.

Aged↗
PubMed1997

Intestinal absorption of sodium dodecyl sulfate in the rodent: evidence for paracellular absorption.

Experiments were performed to define the mechanism of intestinal absorption of dodecyl sulfate (DS), an amphipathic organic anion whose chemical structure resembles that of dodecanoate, a C12 fatty acid anion. With jejunal segments perfused in single-pass fashion in the anesthetized rat, steady-state absorption of DS was concentration dependent, with the apparent permeability constant (P(app)) ranging from 4 to 22 x 10(-5) cm/s. When DS concentration was held constant and net water absorption was induced by decreasing perfusate osmolality, DS absorption increased in direct proportion to water absorption, suggesting absorption by solvent drag via the paracellular route. However, DS absorption continued even when water secretion was induced by a hypertonic perfusate. Consequently, for all experiments, DS absorption could be empirically described as the sum of two terms: 1) absorption in the absence of water absorption (P(app) = 5.6 x 10(-5) cm/s) and 2) absorption induced by water movement [(delta P(app)/delta water absorption) = 0.2 x 10(-5) cm x s(-1) x microl segment(-1) x min(-1)]. In a polarized epithelial monolayer of renal epithelial cells (Madin-Darby canine kidney cells), DS was absorbed predominantly by a paracellular pathway, as the absorption rate increased threefold when paracellular junction pore size was increased by the addition of cytochalasin D. The calculated apparent radius was 2.9 A, indicating that the cross section of the molecule, not its length, determined the rate of absorption. It is concluded that absorption of DS in the intact animal occurs slowly and mostly via the paracellular route, because the fixed negative charge on the molecule retards rapid passive entry into the enterocyte, as occurs with protonated fatty acids. That absorption of DS persisted despite net water secretion suggests a low level of transcellular absorption across the jejunal enterocyte also occurs.

Animals↗
PubMed1997

Carrier-mediated transport of conjugated bile acids across the basolateral membrane of biliary epithelial cells.

When secreted into bile, unconjugated dihydroxy bile acids are absorbed passively by cholangiocytes according to the cholehepatic circulation hypothesis. A fraction of these are likely to be conjugated during transcellular transport. Experiments were performed using fluorescent conjugated bile acids to test whether carrier-mediated transport of conjugated bile acids is present in the basolateral domains of polarized cholangiocytes of intrahepatic bile ductules isolated from rat liver. The time course of the cellular localization of cholyl-NBDAB-Gly and chenodeoxycholyl-NBDAB-Gly, which are anionic fluorescent derivatives of the corresponding glycine-conjugated bile acids, was characterized using an image-analysis system. With 0.3-3 microM solutions, fluorescence was present at 1 and 3 min in the basolateral area of cholangiocytes. Staining in the apical region occurred later, with a peak after 15 min of incubation. The basolateral uptake of the two fluorescent bile acids was temperature dependent and Na+ independent, and was not influenced by the addition of amiloride, by lowering of the medium pH to 6.0, or by preincubation with valinomycin. Uptake was partially inhibited by the absence of Cl- or HCO3- in the perfusate, by preincubation with 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), and by the presence of different organic anions or unconjugated and conjugated bile acids in the medium. When cells were preloaded with an ethyl ester of chenodeoxycholyl-NBDAB-Gly, which is hydrolyzed by intracellular esterases, the decrease of cell fluorescence was partly inhibited by H2DIDS, whereas it was stimulated by the presence of 20 microM cholyltaurine in the medium. It is concluded that transport of conjugated bile acid anions across the basolateral membrane of the polarized rat cholangiocyte is carrier mediated. The conjugated bile acid transporter is likely to be an anion exchanger and is likely to be involved in bile secretion whenever conjugated bile acids or other organic anions are transported from the base of the biliary ductular epithelial cells into the plasma of the periductular capillary plexus.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1996

Bile acid conjugation in early stage cholestatic liver disease before and during treatment with ursodeoxycholic acid.

The efficiency of bile acid conjugation before and during therapy with 600 mg/day of ursodeoxycholic acid was measured in seven adult patients with early chronic cholestatic liver disease (6 with primary biliary cirrhosis; 1 with primary sclerosing cholangitis). Duodenal bile samples were obtained by aspiration and the proportion of unconjugated bile acids was determined using lipophilic anion exchange chromatography to separate bile acid classes, followed by analysis of individual bile acids by gas chromatography-mass spectrometry. The proportion of conjugated bile acids was determined by high-performance liquid chromatography. Use of a (99m)Tc-HIDA recovery marker permitted the absolute mass of unconjugated bile acids in the gallbladder to be calculated. Unconjugated bile acids comprised 0.4% of total biliary bile acids before and 0.2% during ursodeoxycholic acid therapy, indicating highly efficient conjugation of bile acids. During therapy, percentage unconjugated ursodeoxycholic acid significantly increased from (mean +/- S.D.) 13 +/- 13% to 54 +/- 12%; P < 0.002. When the unconjugated and conjugated fractions of bile acids were compared, there was an enrichment in unconjugated fraction for cholic acid and ursodeoxycholic acid and a depletion for chenodeoxycholic acid both in basal condition and during ursodeoxycholic acid therapy, suggesting that hydrophilic bile acids were conjugated less efficiently. During therapy, the conjugation efficiency significantly increased for cholic acid and ursodeoxycholic acid. The pretreatment mass of total unconjugated bile acids in the gallbladder was (mean +/- S.D.) 4.4 +/- 3.2 mumol, and was not significantly changed by ursodeoxycholic acid therapy (6.2 +/- 3.5 mumol). However, ursodeoxycholic acid therapy caused a significant increase in the mass of unconjugated ursodeoxycholic acid. It is concluded that endogenous bile acids and exogenous ursodeoxycholic acid when given at the usual dose are efficiently conjugated in patients with early cholestatic liver disease. Despite showing increased biliary unconjugated ursodeoxycholic acid during its oral administration, our data do not lend support to the occurrence of hypercholeresis due to cholehepatic shunting of bile acids.

Adult↗
PubMed1996

Carrier-mediated jejunal absorption of conjugated bile acids in the guinea pig.

BACKGROUND & AIMS: Conjugated bile acid absorption is known to occur in the jejunum in mammals, but the mechanism has not been well defined. The aim of this study was to define the mechanisms by which conjugated bile acids are absorbed from the jejunum. METHODS: The steady-state absorption of eight conjugated bile acids from a perfused jejunal segment was measured in the anesthetized biliary fistula guinea pig. Experiments defined the effect of bile acid structure, tested for competitive inhibition and saturation of transport, and compared the absorption rate of taurine conjugates with that of glycine conjugates at pH 7.6 or 5.0. RESULTS: Dihydroxy conjugates were absorbed twice as rapidly as cholyl conjugates from the perfused jejunum; glycine and taurine conjugates of a given bile acid were absorbed at a similar rate. Absorption of ursodeoxycholate taurine showed saturability and competitive inhibition by other conjugated bile acids. When intraluminal pH was decreased to pH 5.0, the absorption rate of glycine (but not taurine) conjugates increased, indicating passive absorption of the protonated species of glycine-conjugated bile acids. CONCLUSIONS: Uptake of glycine- or taurine-conjugated bile acids by the guinea pig jejunum occurs by at least two mechanisms: carrier-mediated transport (dihydroxy conjugates greater than trihydroxy conjugates) and passive absorption in protonated (uncharged) form of glycine conjugates.

Animals↗
PubMed1996

Ursodeoxycholic acid and methotrexate for primary sclerosing cholangitis: a pilot study.

OBJECTIVE: Ursodeoxycholic acid (UDCA) and methotrexate (MTX) are both undergoing evaluation for the treatment of patients with primary sclerosing cholangitis (PSC). In this pilot study, we sought to study the safety and estimate of efficacy of a combination of these two drugs administered over a 2-yr period in patients with PSC. METHODS: Nineteen patients with well defined PSC were entered prospectively into a pilot study with anticipation of 2-yr follow-up. The patients received UDCA (13-15 mg/kg/day)in divided doses in conjunction with MTX (0.25 mg/kg/wk). The results of treatment were compared with a concurrently studied, but not randomized, group of 10 patients receiving UDCA alone. At entry, the two groups were comparable with respect to age, sex, liver biochemistries, and histological stage when available. RESULTS: During this period, five patients treated with the combination of UDCA and MTX were severed from the study (three referred for transplantation, one death from small bowel cancer, and one with pre-existing, high ileostomy output who withdrew voluntarily). MTX was discontinued by the investigators in an additional five patients (hair loss in three, pulmonary problems in two). There was no change in fatigue or itching compared with baseline in the group receiving the UDCA/MTX combination. Changes in biochemistries from baseline values were not different in the group receiving UDCA and MTX compared with the group receiving UDCA alone. Furthermore, after MTX was withdrawn and UDCA was continued, there was no clear evidence of further biochemical change. The use of MTX in combination with UDCA was associated with toxicity without any further improvement in liver biochemistries compared with the use of UDCA alone. CONCLUSION: This pilot study found no evidence to support the use of MTX in combination with UDCA for patients with PSC.

Adult↗
PubMed1996

Hepatic biotransformation in rodents and physicochemical properties of 23(R)-hydroxychenodeoxycholic acid, a natural alpha-hydroxy bile acid.

The hepatic biotransformation in the rat and hamster of 23(R)-hydroxychenodeoxycholic acid (23(R)OH-CDCA), the alpha-hydroxy derivative of CDCA, was defined; some physiological and physicochemical properties were also assessed. 23(R)OH-CDCA was isolated from duck bile; [24-14C]23(R)OH-CDCA was synthesized. The compound was administered intravenously to anesthetized biliary fistula rats at doses of 1, 3, or 5 mu mol/kg-min and to hamsters at 3 mu mol/min-kg. Biliary bile acids and radioactivity were analyzed by thin-layer chromatography (TLC), high pressure liquid chromatography (HPLC), and gas chromatography-mass spectrometry (GC-MS). Recovery of radioactivity in bile was incomplete (50-70% of infused dose); some was also recovered as breath 14CO2. Radioactivity in bile was present as unchanged compound (25-50%, dose-dependent) and its conjugates (with taurine, with glycine, or with glucuronate). Nor-CDCA (C23) was present in bile (in both unconjugated and conjugated form), indicating that 23(R)OH-CDCA had undergone oxidative decarboxylation (alpha-oxidation) with loss of the C-24 carboxyl group. The alpha-oxidation was 20 +/- 5% (mean +/- SD) of administered dose in the rat and was not dose-dependent; in hamsters, alpha-oxidation was 35 +/- 8%. In rats, the S isomer of 23OH-CDCA also underwent alpha-oxidation (10 +/- 2%). Nor-CDCA also underwent 6beta-hydroxylation to form nor-alpha-muricholic acid, as well as reduction of its C-23 carboxyl group to form the C23 alcohol. The taurine conjugate of 23(R)OH-CDCA [23(R)OH-CDC-tau] was prepared synthetically and characterized by 1H-NMR. By surface tension measurements, it had a critical micellization concentration (CMC) of 3.5 mM (in 0.15 M Na+), as compared to 1.8 mM for CDC-taurine. Aqueous solubility of 23(R)OH-CDCA increased markedly above pH 5, compared to pH 7 for CDCA. When incubated with cholylglycine hydrolase, 23(R)OH-CDC-tau was deconjugated at a rate one-fourth that of CDC-tau. It is concluded that the presence of a 23(R)-hydroxyl group in a 3alpha, 7alpha-dihydroxy bile acid alters its metabolism in the rodent hepatocyte, as evidenced by inefficient conjugation with taurine or glycine, alpha-oxidation to nor (C23) bile acid, and reduction of the nor bile acid to the primary alcohol. The taurine conjugate of 23(R)OH-CDCA, a major biliary bile acid of marine mammals and wading birds, is a biological detergent with properties superior to those of the taurine conjugate of CDCA. Natural C23 nor-bile acids may be formed by alpha-oxidation of alpha-hydroxy C24 bile acids.

Animals↗
PubMed1996

Validation of [22,23-3H]cholic acid as a stable tracer through conversion to deoxycholic acid in human subjects.

Bile acids labeled with 3H on the sterol nucleus lose a substantial fraction of label during enterohepatic cycling and conversion to secondary bile acids. We tested the isotopic stability of a side-chain 3H label, [22,23-3H]cholic acid in humans. The 3H-labeled compound was administered simultaneously with [24-14C]cholic acid to four healthy volunteers. Duodenal bile was collected daily for 5 days after isotope administration to determine the ratio of 3H/14C in bile acids. Urine was collected to determine loss of radioactivity by this route. Cholic acid and deoxycholic acid were isolated from biliary bile acids by thin-layer chromatography after deconjugation with cholylglycine hydrolase. The ratio of 3H/14C in cholic acid and deoxycholic acid remained constant and identical to that of the administered mixture in all subjects, indicating stability of the 3H label during enterohepatic cycling. Cumulative loss of 3H in urine averaged only 1.2% of administered dose and was identical to loss of 14C (average 1.3%) indicating little if any transfer of 3H from bile acid to body water. Deconjugation of biliary bile acids by alkaline hydrolysis resulted in 15-20% loss of 3H label, consistent with known base-catalyzed exchange of alpha-carbon protons on carboxylic acids. We conclude that [22,23-3H]cholic acid is a biologically stable, and therefore reliable, isotopic tracer of cholic acid in humans during enterohepatic cycling including conversion to deoxycholic acid, provided deconjugation is performed enzymatically. Because the 22,23-3H label can be inserted into most C24 bile acids, it appears the best way to tag 3H-labeled bile acids for metabolic studies.

Adult↗
PubMed1995

Fecal bile acids, short-chain fatty acids, and bacteria after ileal pouch-anal anastomosis do not differ in patients with pouchitis.

Construction of an ileal reservoir changes the fecal bacterial flora and the fecal composition of bile acids and short-chain fatty acids. We examined the relationships between pouch inflammation (pouchitis) and pouch content, as assessed by analysis of fecal bacteria, bile acids, and short chain fatty acids. Four groups were studied: ileal pouch-anal anastomosis (IPAA) for ulcerative colitis with pouchitis (N = 10), IPAA without pouchitis (N =5), IPAA for familial adenomatous polyposis without pouchitis (N = 5); and Brooke ileostomy for ulcerative colitis, which served as controls (N = 5). Pouchitis was defined as > or = 7 points on an 18-point pouchitis disease activity index. Aerobic and anaerobic bacteria were quantitatively cultured. Total aqueous-phase bile acids were measured by thin-layer chromatography and an enzymatic 3 alpha-OH hydroxysteroid dehydrogenase method. Fecal short chain fatty acids were measured by gas liquid chromatography. All patients with an IPAA had higher ratios of anaerobes/aerobes and concentrations of anaerobic gram-negative rods than did patients with an ileostomy. There were no other differences between patient groups with respect to bacteria, aqueous-phase total bile acids, or fecal short-chain fatty acids. Fecal concentrations of bacteria, bile acids, and short-chain fatty acids were similar in patients with and without pouchitis, indicating that these factors can not be the sole cause of pouchitis.

Adenomatous Polyposis Coli↗
PubMed1995

Molecular and functional characterization of an organic anion transporting polypeptide cloned from human liver.

BACKGROUND & AIMS: Based on a recently cloned rat liver organic anion transporter, we attempted to clone the corresponding human liver organic anion transporting polypeptide. METHODS: A human liver complementary DNA library was screened with a specific rat liver complementary DNA probe. The human liver transporter was cloned by homology with the rat protein and functionally characterized in Xenopus laevis oocytes. RESULTS: The cloned human liver organic anion transporting polypeptide consists of 670 amino acids and shows a 67% amino acid identity with the corresponding rat liver protein. Injection of in vitro transcribed complementary RNA into frog oocytes resulted in the expression of sodium-independent uptake of [35S]bromosulfophthalein (Michaelis constant [Km], approximately 20 mumol/L), [3H]cholate (Km, approximately 93 mumol/L), [3H]taurocholate (Km, approximately 60 mumol/L), [14C]glycocholate, [3H]taurochenodeoxycholate, and [3H]tauroursodeoxycholate (Km, approximately 19 mumol/L). Northern blot analysis showed cross-reactivity with messenger RNA species from human liver, brain, lung, kidney, and testes. Polymerase chain reaction analysis of genomic DNA from a panel of human-rodent somatic cell hybrids mapped the cloned human organic anion transporter to chromosome 12. CONCLUSIONS: These studies show that the cloned human liver organic anion transporter is closely related to, but probably not identical to, the previously cloned rat liver transporter. Furthermore, its additional localization in a variety of extrahepatic tissues suggests that it plays a fundamental role in overall transepithelial organic anion transport of the human body.

Amino Acid Sequence↗
PubMed1995

The combination of ursodeoxycholic acid and methotrexate for patients with primary biliary cirrhosis: the results of a pilot study.

Ursodeoxycholic acid (UDCA) and methotrexate (MTX) have both been proposed as treatments for patients with primary biliary cirrhosis (PBC). It has been suggested that a combination of the two drugs may offer advantages over either used separately. In this pilot study, we sought to evaluate the safety and efficacy of this combination for patients with PBC. Thirty-two patients with antimitochondrial antibody positive PBC were prospectively entered into a pilot study and received UDCA, 13 to 15 mg/kg/d, in conjunction with MTX, 0.25 mg/kg/wk, for a period of 2 years. The results of this treatment were compared with those obtained from 180 patients with PBC studied in a placebo-controlled trial of UDCA alone conducted during the same period. Patients in the pilot study and randomized study were comparable with regard to age, gender, and liver biochemistries. The UDCA/MTX-treated patients were of earlier histologic stage and had a lower mean Mayo risk score. During this period, seven patients in the UDCA/MTX group were withdrawn, four for pulmonary toxicity (two who required hospitalization), and one each with mouth ulcer, extreme fatigue, and hair loss. The use of UDCA/MTX was not associated with improvement in symptoms. In the patients receiving UDCA/MTX, biochemical changes were comparable to those of patients receiving UDCA alone but superior to those in the placebo group (P < .05). Histological changes were comparable in all groups at 2 years. Cessation of MTX while UDCA was continued led to no deterioration in liver biochemistries.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Defective biliary secretion during total parenteral nutrition: probable mechanisms and possible solutions.

Cholestasis associated with TPN is now diminishing in frequency. One factor is likely to be the early initiation of oral feeding. One of the effects of oral intake is to restore the enterohepatic circulation of bile acids. This in turn promotes lipid absorption, which leads to improved nutrition and a decreased in mucosal atrophy. The role of the enterohepatic cycling of bile acids has been explored in this review. In infants or children on TPN who have bile acid malabsorption, UDCA can be used to correct decreased secretion of endogenous bile acids. However, controlled studies showing that UDCA actually decreases moribidity and mortality in infants on prolonged TPN have not yet been performed and they are sorely needed. UDCA is nontoxic and acts as a natural bile acid after conjugation. An improved formulation of UDCA with rapid and efficient intestinal absorption has been developed, but the optimal formulation of UDCA is still not available. Cholylsarcosine, a new conjugated bile acid analogue that has been developed as a bile acid replacement agent, improves lipid absorption in animals with steatorrhea caused by bile acid malabsorption and intestinal resection. However, this compound has not been tested clinically.

Adult↗
PubMed1995

Characterisation of patients with a complete biochemical response to ursodeoxycholic acid.

Ursodeoxycholic acid (UDCA) leads to biochemical and clinical improvement in many patients with primary biliary cirrhosis (PBC); although, the response is variable. This study compared UDCA treated patients with complete normalisation of biochemical functions to those without such improvement. Of the 65 patients receiving UDCA, 12 (19%) showed normalisation of liver biochemical functions at two years. The remaining 53 patients showed a less complete response. Mean (SD) alkaline phosphatase and total serum bilirubin values were significantly lower at entry in the patients whose liver biochemistry tests normalised (912 (732) U/l v 1417 (1021) U/l, p = 0.003, and 0.7 (12.1 (5.2) mumol/l v 38.9 (48.5) mumol/l, p = 0.0002, respectively), and percentage of UDCA in biliary bile acid was higher (56.3 (9.5)% v 38.3 (21.1)%, p = 0.03). Patients with biochemically and histologically less severe disease, and greater enrichment of biliary bile with UDCA, are more likely to respond favourably to the drug. The main objective of continued study will be to find out if normal liver biochemical functions can retard disease progression. The association of greater UDCA enrichment with complete biochemical responses suggests that higher doses of UDCA should be evaluated.

Adult↗
PubMed1995

Mast cells and histamine contribute to bile acid-stimulated secretion in the mouse colon.

Certain dihydroxy bile acids cause secretory diarrhea when present in the colonic lumen at inappropriately high concentrations. However, the mechanism underlying the secretagogue activity has not been fully elucidated. Experiments were performed to test whether mast cells and one of their major mediators, histamine, might contribute to the secretory effect. Chenodeoxycholic acid, a secretory bile acid, and ursodeoxycholic acid, a nonsecretory, hydrophilic bile acid, were compared for their ability to induce chloride secretion across segments of mouse colon mounted in Ussing chambers. Chenodeoxycholic acid, but not ursodeoxycholic acid, induced dose-dependent, biphasic chloride secretion that was greater after serosal than mucosal addition and was greater in distal versus proximal colonic segments. The secretory effect of chenodeoxycholic acid was inhibited by H1 histamine receptor antagonists and modified by the cyclooxygenase inhibitor indomethacin. However, it was unaffected by an H2 histamine receptor antagonist or by atropine. Secretory effects of chenodeoxycholic acid were diminished in magnitude and delayed in colonic tissues from mice with a genetic deficiency of tissue mast cells. Concentrations of chenodeoxycholic acid inducing secretion also released histamine from tissue segments. These data indicate that mast cells and histamine-mediated processes contribute significantly to the secretory effects of dihydroxy bile acids in the murine colon.

Animals↗
PubMed1995

Bile acids as drugs: principles, mechanisms of action and formulations.

Bile acid therapy is based on the use of bile acid agonists or bile acid antagonists. Bile acid agonists consist of bile acids or their derivatives. They are used for two purposes. The first is to correct a deficiency in bile acids because of defective biosynthesis or intestinal conservation and thereby to restore bile acid function. This rationale may be termed replacement therapy. The second is to alter the composition of circulating bile acids and thereby to modulate cholesterol metabolism and/or decrease the cytotoxicity of the circulating bile acid pool. This rationale may be termed displacement therapy. Administration of chenodeoxycholic (CDCA) and/or ursodeoxycholic (UDCA) decreases biliary secretion of cholesterol leading to secretion of bile that is unsaturated in cholesterol and gradual dissolution of cholesterol gallstones. Administration of UDCA to patients with chronic cholestatic liver disease lowers the proportion of endogenous cytotoxic dihydroxy bile acids in the circulating bile acids, improves liver tests, and delays liver failure. Bile acid antagonists act to decrease intestinal conservation of bile acids either by sequestering bile acids in the intestinal lumen or by inhibiting bile acid transport by the ileal enterocyte. For therapy, CDCA is administered as the protonated acid and is well absorbed. UDCA is also administered as the protonated acid, but absorption is incomplete. Complete absorption can be obtained using the sodium salt of UDCA in a capsule with a pH-sensitive enteric coating. The taurine conjugate of UDCA is administered as the protonated sulfonic acid, and its absorption requires a carrier mechanism; however, it is likely to undergo rapid deconjugation during enterohepatic cycling, liberating UDCA which can be passively absorbed.(ABSTRACT TRUNCATED AT 250 WORDS)

Bile Acids and Salts↗
PubMed1995

Transport characteristics of three fluorescent conjugated bile acid analogs in isolated rat hepatocytes and couplets.

The transport properties of three different synthetically prepared fluorescent conjugated bile acid analogs (FBA), all with the fluorophore on the side chain, were determined using isolated rat hepatocytes and hepatocyte couplets. The compounds studied were cholylglycylamidofluorescein (CGamF), cholyl(N epsilon-nitrobenzoxadiazolyl [NBD])-lysine (C-NBD-L), and chenodeoxycholyl-(N epsilon-NBD)-lysine (CDC-NBD-L). When hepatocytes were incubated at 37 degrees C with 0.3 mumol/L of FBA and 0.15 mol/L of Na+, cell fluorescence increased linearly with time at a rate (U/min) of 7.8 +/- 0.5 for CGamF, 7.2 +/- 0.3 for C-NBD-L, and 13.7 +/- 1.0 for CDC-NBD-L (mean, +/- SE; n = 40 to 90). Uptake was concentration dependent for concentrations less than 20 mumol/L and was saturable. The Michaelis constant (Km) value (mumol/L) for CGamF was 10.8, for C-NBD-L was 3.8, and for CDC-NBD-L was 3.0. In the absence of Na+, the uptake rate was decreased by 50% for CGamF and by 38% for C-NBD-L; but uptake of CDC-NBD-L was unchanged and thus Na+ independent. Cellular uptake of all three derivatives was specific to hepatocytes and was absent in several nonhepatocyte cell lines. For CGamF and C-NBD-L, both Na(+)-dependent and Na(+)-independent uptake was inhibited by 200-fold excess concentrations of cholyltaurine, dehydrocholyltaurine, and cholate, but for CDC-NBD-L, these nonfluorescent bile acids did not inhibit initial uptake. The intracellular fluorescence of CGamF was strongly pH dependent at an excitation wavelength of 495 nm, but pH independent at 440 nm excitation. In contrast, intracellular fluorescence of C-NBD-L and CDC-NBD-L was pH independent. All three FBA were secreted into the canalicular space of approximately 50% to 60% of couplets. Cellular adenosine triphosphate (ATP) depletion with either CN- or atractyloside inhibited secretion of all three FBA. The multispecific organic anion transporter (MOAT) inhibitor, chlorodinitrobenzene, blocked secretion of fluorescent MOAT substrates at a concentration of 1 mumol/L. At this concentration it did not affect secretion of the three FBA. At higher concentrations, chlorodinitrobenzene partially inhibited the canalicular secretion of CGamF but not the other two FBA. In conclusion, all three FBA are secreted by canalicular membrane bile acid transporters, but the sinusoidal uptake characteristics of CGamF and C-NBD-L are more similar than those of CDC-NBD-L to the transport properties of cholyltaurine. Therefore, C-NBD-L appears to be the best of the three for studies of conjugated trihydroxy-bile acid transport in hepatocytes.

Animals↗
PubMed1995

Simultaneous assessments of exocrine pancreatic function by cholesteryl-[14C]octanoate breath test and measurement of plasma p-aminobenzoic acid.

Two noninvasive tests for assessing pancreatic exocrine function, the cholesteryl-[14C]octanoate breath test and the HPLCN-benzoyl-tyrosyl-p-aminobenzoic acid/p-aminosalicylic acid (NBT-PABA/PAS) test, were simultaneously performed in nine patients with pancreatic exocrine insufficiency due to chronic pancreatitis and in nine healthy volunteers. 14CO2 output in breath and plasma PABA concentration rose slowly in patients but increased rapidly in healthy subjects. The measurement time giving the best discrimination between both groups was 120 min for the cholesteryl-[14C]octanoate breath test and 90 min for the plasma PABA test. At these points, both single-sample tests had essentially identical diagnostic sensitivity. The diagnostic sensitivities of the two single-sample tests were equal to that of the cumulative 6-h urinary PABA recovery and the cumulative 6-h urinary PABA/PAS ratio. We conclude that, for both the cholesteryl-[14C]octanoate breath test and the plasma PABA test, a single test sample is sufficient for rapid detection of impaired exocrine pancreatic function.

4-Aminobenzoic Acid↗