SEARCH · PubMed Health

Results for “Enterohepatic Circulation”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

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

At least 55 records · Page 3Linked to original sources

PubMed2002

A pharmacokinetic model for analysis of drug disposition profiles undergoing enterohepatic circulation.

A new and simple pharmacokinetic model that can explain enterohepatic circulation profiles for both single and repeated dosing was developed, and its applicability and usefulness were assessed by an actual published data set and simulation study. The model is basically a conventional compartment model, and the transfer rate from the bile compartment to the central compartment is assumed to change periodically, with the sine function being used to describe this periodical change. Using this model, the effect of the parameter values on plasma time-course profiles was examined by simulation, and the applicability of the model was tested by curve fitting to obtain the parameter estimates using an actual published data set. These studies confirmed that our model can simulate the periodical increase of the concentration due to re-absorption. By averaging the sine function in the transfer rate from the bile compartment to the central compartment, a smoothed time-course profile in the elimination phase that is independent of the enterohepatic cycle can be obtained. Also, the apparent half-life in the elimination phase can be estimated, whith is useful especially for evaluating drug accumulation during repeated dosing. It was suggested that the present model can be used to evaluate the drug disposition profile with enterohepatic circulation. The effects of sampling points and sampling time on parameter estimation are also discussed.

Absorption↗

PubMed1992

[Pharmacokinetic analysis of enterohepatic circulation of piroxicam in rabbits].

The concentration (c)-time (t) curves of piroxicam showed double peaks following iv 10 mg dose to 4 rabbits. A new mathematical model of enterohepatic circulation was proposed to explain this double-peak phenomenon and showed good agreement with data. This model provides not only the common pharmacokinetic parameters: T1/2 = 1.12 +/- 0.32 h, V1 = 0.64 +/- 0.12 L, AUC = 34.7 +/- 7.8 micrograms.h-1.ml-1, but also the parameters of enterohepatic circulation of piroxicam: the cycling amount of drug Db = 3.9 +/- 1.4 mg, reabsorption fraction Fb = 0.50 +/- 0.04, reabsorption rate constant Ka = 2.55 +/- 0.50 h-1. It is indicated in this study that enterohepatic circulation results in a 20% average increase of the effective amount of piroxicam.

Animals↗

PubMed1979

John Caffey Award: lithiasis due to interruption of the enterohepatic circulation of bile salts.

Bile salts are formed from cholesterol and conjugated in the liver, excreted via the biliary system into the duodenum, reabsorbed in the ileum, stored temporarily in the hepatic bile salt pool, and reexcreted into the biliary system. This normal enterohepatic circulation of bile salts is both efficient and rapid. Interruption of the enterohepatic circulation of bile salts may cause cholesterol cholelithiasis or oxalate urolithiasis. Clinical and radiologic features of pediatric patients with gallstones and urolithiasis secondary to abnormalities of the ileum are reported. The pathophysiology of lithiasis due to interruption of the enterohepatic circulation of bile salts is discussed. This enteric cause is included in the differential diagnosis of cholelithiasis and urolithiasis in infants and children.

Bile Acids and Salts↗

PubMed1986

Enterohepatic circulation and distribution of 131I-6 beta-iodomethyl-19-norcholesterol (NP-59).

The enterohepatic circulation and distribution of 131I-6 beta-iodomethyl-19-norcholesterol (NP-59) was assessed in a rabbit model to examine the relative distribution of NP-59 and its metabolites. Adrenal, bile and serum samples were obtained from seven rabbits at 48 h following NP-59 administration (240 to 570 microCi) and the distribution of 131I radioactivity examined using thin layer chromatography. In serum 71% of the radioactivity circulated as NP-59 and 20% as NP-59 esters. In contrast greater than 90% of the adrenal radioactivity was in the form of NP-59 esters while in bile 70% of the activity was NP-59 with the remainder in the form of bile acids. In another group of animals, adrenal activity was observed 5 days after intragastric administration of NP-59. Thus, we have demonstrated a significant enterohepatic circulation of NP-59 that may have the potential to influence the distribution of and resultant adrenal imaging with NP-59.

19-Iodocholesterol↗

PubMed1982

Intestinal uptake site, enterohepatic circulation, and excretion of tetra- and trialkyltin compounds in mammals.

The intestinal uptake site, enterohepatic circulation, and excretion into bile, feces, and urine of alkyltins (tetra and trialkyltin) were investigated after oral, sc, or intestinal administration of the compounds to rats and rabbits. Assays of tetra- and trialkyltins in biological materials were carried out by gas chromatography. The main uptake sites in the small intestine were the jejunum and duodenum for tetraalkyltins and the ileum and jejunum for trialkyltins. Tetra- and trialkyltins were detected in the small intestine and contents of the intestinal lumen after sc injection of these compounds in rats. These facts suggest that tetra- and trialkyltins are transported in the body through enterohepatic circulation. The route, rate, and amount of excretion of tetra and trialkyltins seem to depend on the velocity of dealkylation, doses, physical and chemical properties, and route of administration of the compounds.

Administration, Oral↗

PubMed1971

Interruption of the enterohepatic circulation of digitoxin by cholestyramine. II. Effect on metabolic disposition of tritium-labeled digitoxin and cardiac systolic intervals in man.

Previous studies of digitalis glycoside metabolism and excretion have indicated that these compounds undergo a significant enterohepatic cycle in some species. It has been suggested that the existence of such a cycle in man contributes to the prolonged action of certain cardiac glycosides. Previous studies have demonstrated that cholestyramine binds digitoxin and digoxin in vitro and accelerates the metabolic disposition of digitoxin in rats and guinea pigs, presumably by interrupting the enterohepatic circulation. In order to assess the role of the enterohepatic circulation in the metabolism of digitalis glycosides in humans, maintenance doses of cholestyramine were administered to 7 of 15 normal human subjects beginning 8 hr after digitalization with 1.2 mg of digitoxin-(3)H. All subjects had frequent measurements of serum radioactivity, left ventricular ejection time (LVET), and electromechanical systole (QS(2)), the latter recorded as the interval from onset of Q wave to first major component of second heart sound. Measurement of the LVET and QS(2) intervals affords a sensitive index of the cardiac response to digitalis. In addition, chloroform extraction of serum was performed to separate unchanged digitoxin and active metabolites from cardioinactive metabolites of digitoxin. Cholestyramine treatment resulted in reduction in half-life to total serum radioactivity from 11.5 to 6.6 days, and in chloroform-extractable radioactivity from 6.0 to 4.5 days, as compared to controls. In addition, cholestyramine treatment was accompanied by more rapid return to base line values of digitoxin-induced changes in the LVET and QS(2) intervals. A significant positive correlation was found between QS(2) values and chloroform-extractable radioactivity, the latter reflecting unchanged digitoxin-H(3) (r=0.64; P=<0.01). The results indicate that administration of cholestyramine to digitalized human subjects accelerates the metabolic disposition of digitoxin and abbreviates the physiologic response to the glycoside. This effect is presumably mediated by interruption of the enterohepatic circulation of digitoxin by cholestyramine.

Administration, Oral↗

PubMedDate not supplied

Effect modelling for drugs undergoing enterohepatic circulation.

A multi-compartment pharmacokinetic model with enterohepatic circulation, was used in simulations and in a clinical trial with morphine. A hypothetical effect compartment was linked to either the central or the peripheral disposition compartment.

Bile↗

PubMed1999

Role of the enterohepatic circulation of bile salts in lipoprotein metabolism.

The enterohepatic circulation of bile salts and cholesterol plays a central role in maintaining whole body cholesterol homeostasis. Hepatic lipoprotein metabolism is reviewed and the role of disturbances in bile salt metabolism in the pathogenesis of dyslipidemias is discussed. Further, the manipulation of bile salt metabolism to treat dyslipidemia is reviewed.

Bile Acids and Salts↗

PubMed1977

The enterohepatic circulation of conjugated bile acids in healthy man: quantitative description and functions.

A multicompartmental model describing the enterohepatic circulation of conjugated bile acids in man under steady-state conditions is proposed. The model encompasses conjugation; deconjugation and reconjugation; dehydroxylation; sulfation, desulfation and resulfation; dehydrogenation; and stereoselective rehydrogenation. A dynamic description of the enterohepatic circulation and a brief description of bile acid functions in health and dysfunctions in disease are also discussed.

Bile↗

PubMed1992

Enterohepatic circulation is essential for regular cycling of duodenal migrating motor complexes in dogs.

The role of enterohepatic circulation and specific bile acids in the initiation and caudad migration of duodenal migrating motor complexes (MMCs) was investigated in conscious dogs. All dogs had spontaneous duodenal MMCs that migrated to the terminal ileum when bile flow was intact. During the first 3 days after total external biliary diversion, no MMCs originated in the duodenum. Instead, all MMCs originated in the jejunum and migrated to the ileum. During the next 4 days of total external biliary diversion, 81% of the MMCs originated in the jejunum and 19% in the duodenum. When normal bile flow was restored after 9 days of total external biliary diversion, regular duodenal MMCs resumed after a delay of 126 +/- 27 minutes. Perfusion of individual bile acids or dogs' own bile, but not saline or alkaline solution, into the duodenum or perfusion of dogs' own bile directly into the ileum during total external biliary diversion restarted duodenal MMCs with a time lag of about 2 hours. The authors conclude that intact enterohepatic circulation is essential for the initiation of regular duodenal MMCs.

Animals↗

PubMedDate not supplied

Effect of enterohepatic circulation on the pharmacokinetics of diflunisal in rats.

The purpose of this study was to examine the effect of enterohepatic circulation on the pharmacokinetics of diflunisal in rats. The "linked animals" experiments provided evidence that diflunisal exhibits an enterohepatic circulation. Within 26 hr after iv administration of diflunisal (10 mg/kg) to rats, excretion was as follows: 42.2% of the dose, bile; 2.3%, unchanged drug; 27.8%, ester glucuronide; and 12.1%, ether glucuronide. On the average, approximately 65% of the amount of the drug and its glucuronides excreted in bile was reabsorbed from the gut. Biliary excretion and plasma data showed that biotransformation of diflunisal to its glucuronides is the rate-limiting step in their elimination. A concentration-dependent decrease in the partial formation clearance to ester glucuronide was observed with decreased concentration of diflunisal. These concentration-dependent kinetics can be at least partly explained by the nonlinear protein binding of diflunisal.

Acylation↗

PubMedDate not supplied

Computer simulation of portal venous shunting and other isolated hepatobiliary defects of the enterohepatic circulation of bile acids using a physiological pharmacokinetic model.

The effect of three isolated defects in the enterohepatic circulation of bile acids on the size and distribution of the bile acid pool, plasma bile acid levels and bile acid secretion into the intestine was simulated using a linear multicompartmental physiological pharmacokinetic model previously used to simulate these aspects of bile acid metabolism in healthy man. Stepwise increases in portal-systemic shunting (with a reciprocal decrease in hepatic blood flow) caused an exponential increase in systemic plasma concentrations of bile acids, but no other major changes in bile acid metabolism. When the effect of varying fractional hepatic extraction was simulated, it was found that the greater the fractional hepatic extraction, the greater the elevation observed for systemic plasma bile acid levels for a given degree of portal-systemic shunting. When total hepatic blood flow was restored to normal by simulating "arterialization," systemic plasma levels of bile acids decreased strikingly, yet remained elevated. For cholate with a fractional hepatic extraction of 0.9 and 100% portal-systemic shunting, arterialization caused a decrease from a 20-fold elevation to a 5-fold elevation. This simulation thus defined the effect of the presence of the portal venous system per se on plasma bile acid levels and also quantified the circulatory route by which substances reach the liver when portal-systemic shunting is present. An isolated defect in hepatic uptake of bile acids caused little change in overall bile acid metabolism other than modestly increased plasma levels. Loss of bile acid storage by the gallbladder caused the majority of the bile acid pool to move from the gallbladder compartments to the proximal small intestine during fasting but had little effect on the dynamics of the enterohepatic circulation during eating. The results of these novel simulations of isolated defects in bile acid transport should aid in the interpretation of the more complex changes in bile acid metabolism which are likely to occur in hepatic or biliary disease.

Bile Acids and Salts↗

PubMed1992

Distinct distributions of D-erythro-neopterin in arteries and veins and its recovery by an enterohepatic circulation.

Large amounts of D-erythro-neopterin, a pteridine derivative, are formed from guanosine triphosphate (GTP) by human macrophages upon stimulation with interferon-gamma. In addition, in humans a basal neopterin level in all body fluids is evident also in absence of immunological stimuli. Extremely high concentrations of D-erythro-neopterin were detected in biliary fluid. We therefore investigated, if an enterohepatic circulation might exist for this substance. We quantified concentrations of pteridines in serum obtained from various vessels and in biliary fluid. Samples were collected during surgery of five patients with duodenal ulcer or adenocarcinoma of the stomach. Our data clearly demonstrate the existence of an enterohepatic circulation for the recovery of neopterin which seems to be specific for this substance. The relative distributions of neopterin concentrations in the gastrointestinal tract and vessels were seen invariably in all patients and were consistent with findings in five corpses examined post mortem. In addition, significantly higher neopterin concentrations, were found in arteries than in veins. The data indicate that neopterin derivatives are consumed in the peripheral capillary system and an enterohepatic circulation is established to maintain constant blood levels of neopterin derivatives. Furthermore, we suppose that the liver is the source of constitutive neopterin concentrations.

Adenocarcinoma↗

PubMed1999

Efficiency of enterohepatic circulation, its determination and influence on drug bioavailability.

A new approach has been developed to determine the factors that influence the balance of drug elimination from the body. This approach is based on 1. a six-compartment-model with compartments connected by different flow rates assuming kinetic processes of first order, 2. on solutions of geometric series and 3. on numerical solutions of a system of non-linear equations. In the model, different ways of drug elimination have been considered: renal, liver and fecal elimination of the drug and its metabolism in the liver. The organs have been characterized by their drug availabilities. Further, the metabolic activity of the liver, the efficiency of drug absorption and re-absorption from the gastrointestinal (GI) tract have been included. This paper identifies three events, characterized by their efficiencies--1. hepatic excretion, 2. elimination of drug from liver into the gall bladder in its non-metabolized form and 3. the re-absorption of the drug from GI tract--as necessary conditions of enterohepatic circulation of (EHC). The product of these efficiencies has been introduced as the efficiency of enterohepatic circulation. Further, the drug bioavailability as a function of the efficiency of EHC is presented. The study shows that--based on the total amounts of non-metabolized drug in urine after p.o. and i.v. administration to animals with and without cannulated bile duct and in the bile of cannulated animals--the efficiency of EHC, bioavailability of the drug, renal and hepatic availability of the drug, metabolic activity of the liver and efficiency of drug absorption and re-absorption from the gut can be determined. Additionally, it has been shown that, depending on the efficiency of enterohepatic circulation, small variabilities in drug pharmacokinetic properties can cause high variance of drug bioavailability. The publication points towards the efficiency of EHC as on a factor that plays a key role in establishing in vitro-in vivo correlation.

Algorithms↗

PubMedDate not supplied

Physiologic cholestasis II: serum bile acid levels reflect the development of the enterohepatic circulation in rats.

We have shown that serum bile acid concentrations are elevated in human infants reflecting physiologic immaturity of the enterohepatic circulation. To define further the ontogeny of bile acid metabolism in mammals, we examined maturational changes in the serum concentration of total cholate conjugates by radioimmunoassay in fetal, neonatal, suckling, and mature Sprague-Dawley rats. Fetal (21st day) levels were low (1.4 +/- 0.23 microM; X +/- S.E.), possibly due to minimal enterohepatic cycling in utero. The concentrations in samples obtained minutes after birth, prior to suckling were significantly elevated (12.6 +/- 2.37; p less than 0.001 vs. fetal); these high values persisted after feeding was initiated (6 hr = 13.5 +/- 0.99), but fell at 12 hr (5.2 +/- 0.81) and remained unchanged for the duration of the first day. Serum values fluctuated briefly, being 9.6 +/- 0.73 on Day 4, and the rose progressively through the suckling period (Day 10 = 7.2 +/- 9.57; Day 14 = 10.4 +/- 1.70; Day 21 = 16.8 +/- 1.93); there was a dramatic peak after weaning (Day 28 = 21.8 +/- 1.53). The serum concentration of cholate conjugates then fell (5.6 +/- 0.68 on Day 42) to achieve adult levels by 56 days (4.0 +/- 0.55), a value substantially different from that of all developing animals (p less than 0.025). These data corroborate studies which suggest that a period of physiologic cholestasis occurs in the developing rat. Serum cholate conjugate concentrations likely reflect interrelated morphologic alterations (bile canalicular structure and portal blood flow) and physiologic changes (bile acid synthesis, pool size, and transport) occurring in the enterohepatic circulation during early life.

Age Factors↗

PubMed1986

Model systems for pharmacokinetics of steroid drugs subject to enterohepatic circulation.

A number of drugs including steroid hormones undergo enterohepatic circulation (EHC) which influences the drug disposition parameters. EHC of drugs leads to prolonged drug exposition which may enhance the risk of liver incompatibility. The extent of EHC expressed by the reabsorption rate of a given drug is of interest from the clinical and toxicological point of view. A two-compartment model with an additional time lag was realized by a hybrid computer system to study the influence of EHC on the shape of plasma concentration-time profiles and pharmacokinetic parameters. Reabsorption rates of potential steroid drugs were calculated by model-simulation and the results compared with the experimentally found ones. Although the lag time model is only a simplified approximation to the underlying physiological processes it reflects sufficiently the pharmacokinetic profile of steroid drugs subject to EHC.

Animals↗

PubMed2004

Pharmacokinetics of flunixin in the cat: enterohepatic circulation and active transport mechanism in the liver.

The plasma and urine pharmacokinetics of flunixin-meglumine (FNX) in cats were examined using a total of 12 adult animals. After an intravenous injection of FNX (2 mg/kg), the plasma concentration time curves showed a profile of a two-compartment open model with an elimination half-life of 6.6 h. In spite of high plasma protein binding (>99%), the V(d)beta was unusually large, 0.7 L/kg. Although the recovery of FNX from urine was only 0.4% of the dose, the estimated inherent renal clearance closely corresponded to the renal plasma flow rate, indicating that a renal active tubular secretion was involved in the pharmacokinetics of FNX. Cholestyramine (ChSA), an anion exchanger, was orally administered immediately before the FNX injection in order to determine the involvement of enterohepatic circulation in FNX pharmacokinetics. The elimination phase of the profile of FNX was prevented by the concomitant administration of ChSA, so it was concluded that the drug undergoes enterohepatic circulation in cats. Pravastatin (PV) is a specific substrate of the type-2 organic anion transporting polypeptide transporter (OATP-2) in human liver cells. The effect of a concomitant intravenous injection of PV with FNX was examined in order to determine the involvement of OATP-2 like transporter in the pharmacokinetics. The V1 and total body clearance were decreased after the injection of PV. In conclusion, at least two active transport mechanisms are involved in the pharmacokinetics of FNX in cats. One pathway is renal tubular secretion and the other is sinusoidal active uptake by liver cells. The latter may be responsible for the enterohepatic circulation of FNX in cats.

Animals↗

PubMed1994

A comparison of two surgical techniques for preparation of rats with chronic bile duct cannulae for the investigation of enterohepatic circulation.

Two surgical biliary cannulation procedures for study of enterohepatic circulation in chronically cannulated rats were compared in a randomized study. Control rats (group A) had only a jugular vein cannula and no laparotomy, whereas experimental group-B rats additionally had the bile duct cannulated at two locations, one for collecting bile from the liver and the other for returning bile into the duodenum. Experimental group-C rats had the jugular vein cannula as well as the bile duct cannula for collecting bile, but the duodenal wall was cannulated for returning bile to the intestine. Several physiologic and biochemical indicators were monitored daily after surgery, including body weight, bile flow rate, and plasma concentrations of bilirubin and creatinine, and activities of glutamate-pyruvate transaminase (GPT) and lipase. Overall duration of survival of group-B rats was shorter than that of group-A rats (P < 0.05), whereas no difference was found between groups A and C. Group-B rats had higher bilirubin concentration than did controls (P < 0.05), whereas group-C rats did not. Group-B rats had higher plasma lipase activity than did rats of the other two groups, and this analyte was more variable in group-B rats. Rats of groups B and C had high GPT activity after surgery (P < 0.05). A statistically significant loss of body weight was associated with group-B rats over 8 days after surgery and for group-C rats over 2 days after surgery, after which body weight stabilized in group-C rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine Transaminase↗