Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Enterohepatic Circulation”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources

The economy of the enterohepatic circulation of bile acids in the baboon. 1. Studies of controlled enterohepatic circulation of bile acids.

A primate model with controlled enterohepatic circulation has been developed which allowed short-term evaluation of bile salt pool size, cycling frequency, and fecal losses. We found that when bile salt secretion into the small bowel was increased above 700 mumol/hr bile acid pool cycling frequency was also increased. The latter allowed short-term regulation of bile salt pool size by affecting increased fecal losses. These compensatory mechanisms were associated with a return of bile acid secretion and cycling frequency to normal usually within 12-24 hours. Conversely, during decreased bile salt secretion, regulation of bile salt pool size was accomplished by decreased pool cycling, which decreased fecal losses. Bile acid secretion into the intestine was therefore a major determinant of bile salt cycling frequency. The latter affected bile salt fecal loss to provide short-term regulation of bile salt pool when feedback regulation of bile salt synthesis was nonoperative.

Animals↗

Canine bile acid enterohepatic circulation.

The enterohepatic circulation (EHC) of bile acids has been studied in fasting dogs with portacaval shunt maintained in the steady state. In such animals the rate of EHC is proportional to systemic blood bile acid concentration. Bile acid EHC was irregular (20 to 100% variation) when measured at 15 minute or hourly intervals. Studies showed that the variations persisted in cholecystectomized and sphincterectomized animals. The irregularities were enhanced by bethanechol chloride which increases intestinal peristalsis and suppressed by diphenoxylate HCl which slows peristalsis. The variations appear to arise from irregular patterns of intestinal peristalsis. This phenomenon may explain some variations in blood bile acid concentration observed in patients with liver disease.

Animals↗

The economy of the enterohepatic circulation of bile acids in the baboon. 2. Regulation of bile acid synthesis by enterohepatic circulation of bile acids.

Isotope dilution within bile acid pools and radiochemical assessment of cholesterol oxidation to bile acids were methods used to measure short-term feedback regulation of bile acid synthesis in baboons with controlled enterohepatic circulations. Intraduodenal infusion of labeled endogenous bile acid pools into bile acid-depleted animals with enhanced bile acid synthesis showed that the rate of bile acid returned to the liver affected the degree of inhibition of bile acid synthesis. Infusion of prepared bile acid pools of varying composition resulted in a specific pattern of feedback inhibition of bile salt synthesis related to pool composition and mass. Individual bile salts inhibited their own synthesis more than that of other bile salts, and chenodeoxycholic and deoxycholic acids were found to have greater inhibitory effects than cholic acid. Glycine-conjugated cholic and chenodeoxycholic acids had greater inhibitory effects than did the respective free bile salts. Infusion of mixed bile acid pools showed that dihydroxy bile acids (chenodeoxycholic or deoxycholic) enhanced feedback inhibition of cholic acid. In all studies, inhibition of bile acid synthesis occurred twice as fast as its derepression.

Animals↗

Bacterial metabolism of natural and synthetic sex hormones undergoing enterohepatic circulation.

Steroids undergoing enterohepatic circulation are exposed to bacterial metabolism particularly by obligate anaerobes which account for 99.99% of the fecal flora. The most common transformation is hydrolysis of conjugated steroids. The glucuronidases are synthesized by Escherichia coli and Bacteroides species. The bacterial catabolism of unconjugated steroids may be considered under several headings: 1. Reduction of ring-A due to clostridia species synthesizing specific enzymes; C. paraputrificum, 3 alpha,5 beta-reductase; C. innocuum, 3 beta,5 beta-reductase; and a new species C.J-1, 3 beta,5 alpha-reductase. 2. Reduction of the delta 5 bond by human fecal flora. The specific strain(s) synthesizing the enzyme have not yet been identified. 3. Reduction of 17-keto estrogens by the above mentioned ring-A reducing clostridia and by Eubacterium lentum. 4. Reduction of 17-keto androstenes by Bacteroides fragilis. 5. Desmolase mediated side chain cleavage at C17-C20 position of 17 alpha-hydroxysteroids by two new species Clostridium scindens and Eubacterium desmolans isolated from human and cat fecal flora respectively and by Clostridium cadavaris isolated from New York City sewage. 6. And 16 alpha- and 21-dehydroxylase by E. lentum a normal inhabitant of the human gut; it is the only organism known to synthesize 16 alpha- or 21-dehydroxylases. Due to the high specificity of the enzymes and the simplicity of extracting the metabolites, biosynthesis of reference compounds and radioimmunoassay reagents is practical and inexpensive. The enzymes can also be used for titration of specific bacterial strains in fecal flora and as markers for bacterial identification in particular for the strains difficult to be defined by regular biochemical reactions.

17-Ketosteroids↗

Kinetic analysis of glycyrrhetic acid, an active metabolite of glycyrrhizin, in rats: role of enterohepatic circulation.

The role of enterohepatic circulation of glycyrrhetic acid (GA) in rats was determined by kinetic analysis of GA. The concentrations of GA in the plasma of the control rat (without bile duct cannulation) during the first 5 h after intravenous (iv) administration of GA (2, 5, 10, and 20 mg/kg) were similar to those in the bile duct-cannulated rat at each dose. No significant difference was observed in the values of the terminal half-life, the total body clearance, the distribution volume at steady state, the area under the curve of concentration in plasma versus time, and the mean residence time in each dose between both groups. When GA (2, 5, 10, and 20 mg/kg) was administered i.v. to the bile duct-cannulated rat, excretion of unchanged GA in bile was < 1% of each dose, that of the acid-hydrolyzed products was 14-16%, and that of GA-3-O-glucuronide was only 1-2%. In the control rat, a secondary peak of GA concentration was observed 12 h after i.v. administration of GA (20 mg/kg). The enterohepatic circulation of GA was confirmed by the linked-rat method in which bile of the donor rat after i.v. administration of GA (20 mg/kg) was allowed to flow directly into the duodenum of the recipient rat. GA was found in the plasma of the recipient rat after 6 h, and its concentration reached the maximum (approximately 0.5 microgram/mL) 8-12 h after dosing the donor rat.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Enterohepatic circulation model for population pharmacokinetic analysis.

An enterohepatic circulation model based on physiological aspects of biliary excretion has been developed for population pharmacokinetic analysis. Mycophenolate mofetil was selected as a model drug for validation of the model. As a secondary objective, the model was used for pharmacokinetic comparison among different races. The post-hoc plasma concentration-time course was well described by the newly developed enterohepatic model and a secondary peak arising from enterohepatic circulation was also well defined. The covariates predicted by the model agreed well with literature results. The model is useful for evaluation of the covariates of an enterohepatically circulated drug. The population pharmacokinetic approach is of benefit for evaluating racial differences for a pharmacokinetic bridging package.

Adult↗

A new analysis method for disposition kinetics of enterohepatic circulation of diclofenac in rats.

The pharmacokinetics of diclofenac, which is definitely subject to enterohepatic circulation in rats, was evaluated. The pharmacokinetic model for enterohepatic circulation was constructed in the Laplace-transformed domain by means of the transfer function method of the signal flow. The transformed equations were simultaneously fitted to the time courses of plasma concentration averaged over two groups of rats [i.e. one with an intact enterohepatic circulation and the other without an enterohepatic circulation by means of the bile duct cannula (double-lines fitting)]. The transformed equations were also fitted to each plasma time course in the individual rat (single-line fitting). It was demonstrated that the estimated pharmacokinetic parameters by the single-line fitting almost coincided with those by the double-lines fitting. The local moments for a single pass through enterohepatic circulation were also calculated from the time courses of both the plasma concentration and the amount excreted into the bile. In the nonanesthetized group, the recirculation ratio (Fc) and the mean recirculation time (tc) of diclofenac were estimated to be 21.1% and 4.5 hr, respectively. The absorption ratio (Fa) and the mean absorption time (ta) from the intestinal tract were 52.2% and 4.29 hr, respectively. The experiments using bile duct cannulation revealed that the total amounts excreted into the bile were 14.4% in the anesthetized group and 40.4% in the nonanesthetized group of rats, and that diclofenac was excreted 95% as the glucuronide form and 5% as the intact form in both groups.

Animals↗

Alternative continuous infusion method for analysis of enterohepatic circulation and biliary excretion of cefixime in the rat.

The enterohepatic circulation and biliary excretion of cefixime during continuous infusion were evaluated in rats based on the recirculatory concept. The Laplace-transformed equations for the enterohepatic circulation according to this concept were derived by means of the combination of transfer function. The transformed equations were simultaneously fitted to the time courses of plasma concentration in rats with laparotomy and with bile duct cannula by means of a nonlinear regression program, MULTI(FILT), into which the fast inverse Laplace transform was incorporated. The optimum model was selected on the basis of Akaike's information criterion (AIC). The time course of drug accumulation in the bile during infusion starts with a relatively gentle slope and finally approaches the asymptote with a constant slope. The kinetic significance of this asymptote was explained using the time courses of the cumulative amount excreted into the bile of rats with bile duct cannulation. The local moment characteristics for a single pass through enterohepatic circulation were further calculated from the time courses of both the plasma concentration and the excreted amount into the bile. The recovery ratio (Fc) and the mean circulatory time (tc) through a single pass of enterohepatic circulation were estimated to be 31.1% and 0.925 h, respectively. The recovery ratio (Fa) and the mean transit time (ta) for the complicated process from the access to the bile duct into the systemic circulation such as transport through the bile duct, absorption from the intestinal tract, and transit through the portal system were 76.4% and 0.0231 h, respectively. The recovery ratio (Fb) and the mean transit time (tb) for the disposition process through the systemic circulation into the bile were 40.7% and 0.902 h, respectively.

Animals↗

Pharmacokinetic study of the enterohepatic circulation of acetaminophen glucuronide in rats.

A pharmacokinetic model of the enterohepatic circulation of acetaminophen glucuronide was investigated in rats with particular attention to a lag time between biliary excretion and reabsorption. The plasma drug data obtained after acetaminophen glucuronide injection into the various sites of the gut confirmed that there is a lag time in the enterohepatic circulation and that the lag time is due to the intestinal transit period of the conjugate to the site of the hydrolysis. The value of the lag time was fairly close to that reported previously in the rat. Based on the result, a compartment model with periodic trigonometric function for the enterohepatic circulation was built up and the urinary excretion data were fitted to this model. Same parameters which are considered to be common to other glucuronide conjugates were in good agreement with those reported previously, indicating that the model and those values are useful to study the enterohepatic circulation for glucuronides of other compounds in the rat.

Acetaminophen↗

Role of enterohepatic circulation in the analgesic action of 1-alpha-acetylmethadol in the rat.

The enterohepatic circulation of 1-alpha-acetylmethadol (LAAM) was investigated in the rat. Bile containing 3H-LAAM metabolites was collected from a biliary cannulated donor rat after administration of 3H-LAAM (5 mg/kg, 15 muCi/kg, sc) and infused into the intestine of a double biliary-cannulated recipient rat for 1 hr, and tritium excreted into the bile of the recipient rat was monitored. Within 1 hr after the end of infusion significant radioactivity was found in the bile of the recipient rat and by 10 hr 50% of the infused dose of 3H had been re-excreted into bile. The contribution of enterohepatic circulation of LAAM metabolites to the analgesic action of LAAM was also assessed. Pretreatment of rats with neomycin sulfate was used as a method of decreasing enterohepatic circulation of biliary glucuronide conjugates of LAAM metabolites, and such pretreatment had no effect on LAAM analgesia (6 mg/kg) measured by the hot-plate method. In rats with a biliary fistula, a situation in which enterohepatic circulation was completely eliminated, the analgesic response to a dose of LAAM (6 mg/kg, sc) was not different from sham-operated control group. The above findings indicate that enterohepatic circulation of LAAM metabolites does not contribute to the intensity or duration of LAAM analgesia.

Analgesics↗

Biliary secretion in conscious rabbits: role of the enterohepatic circulation of bile salts and of the gall bladder.

The role of enterohepatic circulation of bile salts in biliary secretion in conscious rabbits has been investigated before and after cholecystectomy. Bile flow was higher and bile salt concentration lower in cholecystectomized than in intact rabbits: this could have been caused by a negative feed-back effect on bile salt synthesis as the circulating bile salt pool increased. The effects of cholecystectomy on flow and bile salt concentration balanced each other. Bile flow and bile salt concentration declined after interruption of the enterohepatic circulation in both cholecystectomized and intact rabbits. Furthermore, the percentage of the flow of bile independent of bile salt secretion increased, while that independent of total analysed solutes decreased after the enterohepatic circulation was broken. These results confirm that the decrease in bile flow after interruption of the enterohepatic circulation is due to loss of bile salts and not of electrolytes.

Animals↗

The enterohepatic circulation of bile acids in man.

The enterohepatic circulation of bile acids may now be described in its broad outlines. Methodology presently available appears sufficient for overall characterization in health and disease. The challenge of the future is to gain insight into the control of the enterohepatic circulation so that new therapeutic approaches to liver, biliary and intestinal disease may be developed.

Amino Acids↗

Analysis of enterohepatic circulation of cefixime in rat by fast inverse Laplace transform (FILT).

The enterohepatic circulation of cefixime in rat was evaluated by a nonlinear least square analysis program, MULTI(FILT), into which the fast inverse Laplace transform (FILT) was incorporated. The plasma time course in the bile duct-cannulated rat exhibited a biexponential curve after the rapid iv administration of cefixime. Several pharmacokinetic models for the enterohepatic circulation were constructed based on the recirculatory concept and the Laplace-transformed equations corresponding to these models were derived by means of the method of transfer function. The transformed equations were simultaneously fitted to the time courses of plasma concentration in rats with laparotomy and with bile duct cannula. The optimum model was selected based on the Akaike's information criterion (AIC). The local moment characteristics for a single pass through enterohepatic circulation were further calculated from the time courses of both the plasma concentration and the amount excreted into the bile. The recovery ratio (Fc) and the mean circulatory time (-tc) through a single pass of enterohepatic circulation were estimated 27.9% and 1.07 hr, respectively. The recovery ratio (Fa) and the mean absorption time (-tc) for the absorption process from the intestinal tract into the systemic circulation were 68.3% and 0.0234 hr, respectively. The recovery ratio (Fb) and the mean transit time (-tb) for the disposition process through the systemic circulation into the bile were 40.8% and 1.05 hr, respectively.

Animals↗

Enterohepatic circulation of newly administered alpha-tocopherol in the rat.

We have measured the magnitude of the enterohepatic circulation of newly administered [3H]-alpha-tocopherol in rats. One group of animals (day-1 rats) was used to prepare [3H]-alpha-tocopherol-containing lymph. Another set of animals (day-2 rats) was divided into control and vitamin E supplemented (+E) groups, which were used to study the enterohepatic circulation of [3H]-alpha-tocopherol from day-1 rat lymph administered into the jugular vein of day-2 rats. Mesenteric lymph duct and common bile duct cannulations were performed. The enterohepatic circulation in day-2 rats of intrajugularly administered [3H]-alpha-tocopherol in chylomicrons was found to be 1.78 +/- 0.23% for control and 0.98 +/- 0.08% for +E rats (p less than 0.01). A considerable quantity (13.3 +/- 4.3% in control vs 19.2 +/- 4.7% in +E) of [3H]-radioactivity was recovered in bile over 24 h, of which pure [3H]-alpha-tocopherol was 3.17% in control and 1.04% in +E bile. More than 95% of [3H]-radioactivity recovered in day-2 control and +E bile was more polar than alpha-tocopherol shown by high performance liquid chromatography (HPLC). In contrast, more than 95% of [3H]-radioactivity appearing in day-2 lymph was unchanged alpha-tocopherol. Thus, the magnitude of enterohepatic circulation of alpha-tocopherol is very small in rats. Quantitation of the enterohepatic circulation of vitamin E under different physiological conditions remains to be investigated.

Animals↗

Enterohepatic circulation of l-alpha-acetylmethadol in the rat.

The enterohepatic circulation of the biliary metabolites of l-alpha[3H]acetylmethadol ([3H]LAAM) was studied in rats. Bile was collected for 48 hr from a biliary-cannulated donor rat after s.c. administration of [3H]LAAM. This bile containing tritium-labeled LAAM metabolites was then infused into the small intestine of a recipient rat for 48 hr and the appearance of radioactivity in bile formed in the liver of the recipient rat was monitored. Forty-eight hours after the start of infusion, 40% of the infused radioactivity had been excreted into the bile of the recipient rat, indicating extensive enterohepatic circulation of the biliary metabolites of LAAM. The data indicated that only a small percentage of the infused [3H]LAAM metabolites were present in the systemic circulation at any one time. This was further investigated by comparing the plasma levels of tritium with time and the tissue concentrations at 24 and 48 h after s.c. [3H]LAAM administration in biliary-cannulated and sham-operated control rats. Complete diversion of the bile did not significantly decrease the levels of [3H]LAAM or its metabolites in the systemic pool. These findings tend to minimize the contribution of enterohepatic circulation in the recirculation of active metabolites of LAAM and ultimately in its long duration of opiate-like action.

Animals↗

Pharmacokinetic analysis of enterohepatic circulation of 4-[2-(4-isopropylbenzamido)ethoxy]benzoic acid. Effect of intramolecular rearrangement of its acyl glucuronide.

The enterohepatic circulation of 4-[2-(4-isopropylbenzamido)ethoxy]benzoic acid (PBAB) was studied in rats after an iv administration of 30 mg/kg. After the bolus injection, the PBAB concentrations in the plasma decreased rapidly, then increased to a peak concentration at 4 hr. Over a 6-hr period, 52% of the dose (Fe) was excreted in the bile as 1 beta-O-acyl glucuronide of PBAB (1 beta-PG). Elimination of PBAB from the plasma of bile duct-cannulated rats was more rapid than for the sham-operated rats. These results suggest that PBAB undergoes enterohepatic circulation. The equation for an enterohepatic circulation model was fitted to the plasma PBAB concentrations for intact rats using the program MULTI (FILT) to estimate the single circulating fraction (Fc) (bile----intestine----systemic circulation). The Fc value was 0.072, which means that 7.2% of the dose was reabsorbed to systemic circulation during the first cycle. The fraction (Fa) reabsorbed from small intestine to systemic circulation during first cycle can be estimated by the formula Fa = Fo/Fa. The Fa value obtained was 14% of the dose, which was smaller than the Fa' (26% of the dose) standing for systemic availability of PBAB after oral dosing. When 1 beta-PG was incubated with bile for 2 hr, 79% was transformed to beta-glucuronidase-resistant isomers by intramolecular acyl migration. We consider that the acyl migration of 1 beta-PG in the small intestine or bile causes the difference between Fa and Fa' values, and decreases the enterohepatic circulation of PBAB.

Animals↗

Biliary response to food in rabbits: role of the gall bladder and the enterohepatic circulation of bile salts.

The biliary response to feeding has been investigated in intact and cholecystectomized rabbits, with and without interruption of the enterohepatic circulation of bile salts. The relative contribution of the different secretory mechanisms involved in this process has been examined. Feeding induced an increase in the flow and bicarbonate concentration of the bile and a slight decrease in the bile salt content in rabbits with gall bladders and the enterohepatic circulation intact. Feeding with the enterohepatic circulation interrupted elicited a drop in bile flow and the bile salt concentration, but an increase in bicarbonate concentration. Interruption of the enterohepatic circulation thus dramatically modifies the feeding response: a response to food is still detectable after interruption, but is masked by the negative effects of drainage of the bile away from the duodenum.

Animals↗

Review article: the 'mechanical pumps' and the enterohepatic circulation of bile acids--defects in coeliac disease.

Bile acid pool size is maintained relatively constant at about 3-5 g in healthy subjects by two mechanisms, enterohepatic circulation and de novo synthesis of bile acids. This latter mechanism compensates for the daily faecal loss (about 0.2-0.6 g) of bile acids, whereas the bulk of the pool is conserved by the former mechanism. The driving forces of the enterohepatic circulation are constituted by chemical pumps, including intestinal absorption and hepatic uptake, and by mechanical pumps, including gall-bladder and intestinal motility. The latter provide the main propulsive forces for bile acids to reach the site of intestinal absorption, and by contrast with the very rapid chemical pumps, mechanical pumps have storage capacity for the bile acid pool and therefore comprise the slow limb of the enterohepatic circulation. In coeliac disease, a disease classically described as a malabsorption syndrome associated with mucosal atrophy of the small intestine, both gall-bladder and small intestinal motor functions are impaired, and in this article we review the mechanisms involved in these defects, how they influence the enterohepatic circulation of bile acids, and the evidence supporting the concept that both the gall-bladder and the small intestinal motor functions represent the main factors affecting the kinetics of the enterohepatic circulation.

Bile Acids and Salts↗