Enterohepatic circulation and pharmacokinetics of genistin and genistein in. View the article pdf and any associated supplements and figures for a period of 48 hours. The enterohepatic circulation ehc is defined as a process that is composed of a circuit of several steps including. Enterohepatic circulation of glucuronide metabolites of. Drugs entering the intestinal tract may be absorbed into the portal circulation where they can be removed from systemic circulation by hepatic uptake. Physiological, pharmacokinetic and clinical implications. Pharmacokinetics of drugs subject to enterohepatic. The role of human carboxylesterases in drug metabolism. Enterohepatic circulation of vitamin d metabolites and their conjugates will be also discussed. The influence of the changes in biliary excretion and reabsorption rates on the pharmacokinetics of drugs subject to enterohepatic circulation was examined analytically. Ehc of a compounddrug occurs by biliary excretion and intestinal reabsorption, sometimes with hepatic conjugation and intestinal deconjugation. As a secondary objective, the model was used for pharmacokinetic comparison among different races.
Induction and inhibition of drug metabolism inhibition of. Enterohepatic circulation ehc is a process composed of a circuit of hepatic metabolism, biliary excretion, gut microbiome metabolism, followed by reabsorption from the gut back to systemic circulation. Cytochrome p450 3a4 cyp3a4 is a multifunctional enzyme involved in both xenobiotic and endobiotic metabolism. Modeling and experimental studies of obeticholic acid. Bioavailability is also affected by the extent of intestinal absorption, gutwall pglycoprotein efflux and gutwall metabolism. Phospholipids, the other major lipid class in bile, resemble cholesterol in that a small percentage of biliary lecithin, which passes into the intestine, may find its way back to the bile. Enterohepatic circulation is an especially important concept in the field of toxicology as many lipophilic xenobiotics undergo this process causing repeated liver damage. Enterohepatic circulation of radioactivity following an. A study of enterohepatic circulation in vivo was made by comparing removed from a rat under pentobarbital anesthesia, washed with krebsthe pbab concentrations in the plasma ofshamoperated and bile duct ringer bicarbonate solution ph 7. Also, ehc plays a detrimental role as the compounds drugs are allowed to recycle. Oca plasma levels were measured in healthy volunteers and cirrhotic subjects. After intravenous administration of 3hbuprenorphine 100.
Substances are said to undergo an enterohepatic circulation ehc when they. Active drug can be reabsorbed in a process called enterohepatic circulation. Ehc may be regarded as a distribution phenomenon to the extent that the drug secreted in bile is ab sorbed back into the portal circulation. Enterohepatic circulation of glucuronide metabolites of drugs in dog. A recently proposed twocompartment model with drug elimination occurring in each compartment was adapted to.
Turnover of exchangeable cholesterol theexchangeable pool ofcholesterol participates in an incomplete enterohepatic circulation, in which cholesterol is excreted via the bile duct into the. In normal rats, 4enevpa was recycled in the plasma due to enterohepatic circulation ehc. Request pdf enterohepatic circulation enterohepatic recycling occurs by. The enterohepatic circulation of radioactive material after administering 14ctemazepam was evaluated in three sets of male wistar strain rats connected in pairs by bile duct. Intestinal reabsorption to complete the enterohepatic cycle may depend on hydrolysis of a drug conjugate by gut bacteria. Enterohepatic circulation an overview sciencedirect topics. The role of pharmacogenetics in the function of drug transporter proteins. Cycling is often associated with multiple peaks and a longer apparent halflife in a plasma concentrationtime profile. Pharmacokinetics and enterohepatic circulation of 2n. For an hce2 substrate drug that undergoes high firstpass hydrolysis in the small intestine, the subsequent fate after absorption into the systemic circulation is less clear. It was primarily metabolized by cyp3a4 and ugt1a9 and about 71% of a single radiolabeled dose 24% as metabolites was excreted in feces. Enterohepatic circulation involves substances that are metabolized in the liver, excreted into the bile, and passed into the intestinal lumen. Pharmacogenetics of drug transporters in the enterohepatic circulation.
Enterohepatic circulation drugs are inactivated by glucoronidation in liver and these glucoronides are delivered via bile into intestine where they are hydrolyzed releasing the active drug. Bile salts secreted by the liver pass into the intestine, are absorbed in large part by the ileum, and return to the liver by way of the portal vein, thus completing a portal enterohepatic circulation ehc. Timeactionprofilebloodlevels route onset peak duration. Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems. Induction and inhibition metabolism based drugdrug and other interactions can have a significant influence on the use and safety of many drugs. More generally, xenobiotic metabolism from the greek xenos stranger and biotic related to living beings is the set of metabolic pathways that modify the chemical structure of xenobiotics, which are compounds foreign to an organisms normal biochemistry, such as any drug. The effect of this enterohepatic circulation is to prolong the life of the drug in the body. Enterohepatic circulation refers to the circulation of biliary acids, bilirubin, drugs or other substances from the liver to the bile, followed by entry into the small intestine, absorption by the enterocyte and transport back to the liver. The metabolism of retigabine in humans and dogs is dominated by n glucuronidation mcneilly et al. This cycle prolongs the residence of active drug in the body.
Enantioselectivity of the enterohepatic recycling of. Factors affecting biliary excretion include drug characteristics chemical structure, polarity and molecular size, transport across sinusoidal plasma. Ehc represents a complementary nonrenal route to excrete unwanted substances. Since the liver is a major site of drug metabolism. A time lag pharmacokinetic model was used to describe the plasma profile, including the appearance of a secondary plasma peak, in normal animals receiving the low dose of 4enevpa. After phase i detoxification in the liver, many environmental toxins are excreted in bile and undergo. A drug, which is either biologically active itself or a prodrug, may be excreted in its original chemical state. Ativan lorazepam injection food and drug administration. The enterohepatic circulation ehc of drugs is often the result of the direct. Ehc can be an ignored elimination pathway that could have significant clinical implications.
An extraportal ehc also exists, which is minor in health but may become a major determinant of bile metabolism in disease. Environmental toxins, drug metabolism, and the microbiome. Mycophenolate mofetil was selected as a model drug for validation of the model. Enterohepatic recycling occurs by biliary excretion and intestinal reabsorption of a solute, sometimes with hepatic conjugation and intestinal deconjugation. A reversible clearance model for the enterohepatic. Alternatively, all or a portion of a drug may undergo chemical modification and be eliminated as biologically active, or inactive, metabolites see the record on drug biotransformation.
Retigabine nglucuronidation and its potential role in. Altered drug metabolism and elevated serum bile acids in. A physiologic pharmacokinetic model was developed to quantitatively describe the adme of. Enterohepatic circulation ehc is a process composed of a circuit of hepatic metabolism, biliary excretion, gut microbiome. Following extravascular dosing, drug absorption is generally more rapid than drug elimination. Enterohepatic circulation request pdf researchgate. Figure 7 bile acid metabolism and enterohepatic circulation of bile acids. This paper offers the largest data pool of those drugs undergoing ehc.
Studies in dogs with diverted bile flow showed that both enantiomers were extensively excreted in bile with 74% of the renantiomer and 92% of the senantiomer from the iv administered. Enterohepatic circulation ehc is a process composed of a circuit of hepatic metabolism, biliary excretion, gut microbiome metabo. Induction of drug metabolism can lead to unexpected drops in drug concentration or the buildup of metabolites. Enterohepatic circulation ehc prolongs the halflife of a drug in blood. Interruption of this socalled enterohepatic circulation of vitamin b 12 causes the body to go into a significant negative balance for the vitamin. In adult humans, the enterohepatic circulation maintains a bile acid pool size of 50 to 60 mmol per kg body weight, corresponding to approximately 2 to 4 g. The presence of ehc results in longer apparent drug halflives and the appearance of multiple secondary peaks. Figure 1 depicts different pathways of drug absorption from gastrointestinal tract to systemic circulation. An enterohepatic circulation model based on physiological aspects of biliary excretion has been developed for population pharmacokinetic analysis. Enterohepatic circulation, clinical pharmacokinetics 10.
Interplay between vitamin d and the drug metabolizing. The disposition of the two enantiomers of carprofen cpf, the rcpf and the scpf, was investigated after iv administration of the racemate 4 mgkg in dogs equipped with a chronic bile duct catheter. Of all the conjugated anions secreted into bile, only bile acids are actively absorbed in conjugated form and undergo an enterohepatic circulation. Hepatic excretory function removal of organic compounds both endogenous and exogenous via metabolism followed by excretion through bile duct. Factors affecting biliary excretion include drug characteristics chemical structure, polarity and molecular size.
Role of enterohepatic recirculation in drug disposition. Drug excretion is the process of eliminating a drug from the body. An overview of the hostmicrobiome model of drug metabolism drugmetabolizing activity by host and microbiome can result in the same drug metabolites, which. The comparison of the in vivo and in vitro kinetics of retigabine n glucuronidation in these species identified a constant ratio between retigabine and retigabine n. Such drugs are secreted from the liver into bile by active transporters, then into duodenum.
Substances are said to undergo an enterohepatic circulation ehc when they are excreted into the bile, pass into the lumen of the intestine, are reabsorbed and then return to the liver via the circulation. Induction and inhibition of drug metabolism inhibition of biliary excretion by nagaraju b 2. Reviews drug discovery today volume 19,number 3 march 2014 drug enterohepatic circulation and disposition. Enterohepatic circulation is a wellcharacterized mechanism for biochemical exchange between the gut microbiota and the host. Enterohepatic recirculation ehc concerns many physiological processes and notably affects pharmacokinetic parameters such as plasma halflife and auc as well as estimates of bioavailability of drugs. After intramuscular administration of 3hbuprenorphine to rats, dogs, rhesus monkeys and one human volunteer, most of the dosed radioactivity was excreted in the faeces, indicating biliary excretion and a possible enterohepatic circulation of the drug in these species. Thus, for drugs undergoing biliary excretion, ehr represents a. Some drugs undergo reabsorption back into systemic blood circulation enterohepatic circulation. The measurement of the amount of the drug in the plasma at periodic time intervals indirectly indicates the rate and extent at which the.