Mechanisms of impaired biliary excretion of acetaminophen. Little is known yet about the biliary excretion mechanism of asialoglycoproteins. Biliary excretion and choleretic effect of cefmetazole. The importance of conjugation for biliary excretion is clearly shown by the fact that bsp excretion is decreased following depletion of glutathione hepatic content by diethyl maleate 8, 9, iodomethane 25 and administration of a proteinfree diet 26 or when glutathione 5transferase activity is inhibited by benzodiarone 27, organic analogs of metals 28 and hypolipidemic drugs 10,11. Hepatic processing of transforming growth factor beta in. This seems to indicate that coupling of methyl mercury to glutathione in the liver before biliary excretion is a glutathione s. Pbpk modeling of coproporphyrin i as an endogenous. This study was designed to establish a strategy to predict drug interactions involving biliary excretion.
Xenobiotics inhibit hepatic uptake and biliary excretion of. All patients had undergone cholecystectomy and exploration of the common bile du. Intestinal heme oxygenase inhibition and increased biliary. The median concentration of ciprofloxacin n 9 was 2.
Induction and inhibition of drug metabolism inhibition of. The bile then transports the drugs to the gut, where the drugs are excreted. Within 12 hours, csa treatment concomitantly increased intracellular concentrations iccs of gca and fgf19 mrna content, an fxrtarget gene. Biliary excretion of drug and metabolites involves one of several atpdependent transport proteins expressed on the canalicular membrane.
Because the biliary excretion is a major elimination pathway for cpt11 and its metabolites an active metabolite, 7ethyl10hydroxycamptothecin sn38, and its glucuronide, sn38glu, several. Biliary excretion of parent drugs is a less prevalent clearance pathway. Choleresis and inhibition of biliary lipid secretion induced. The type of sugar moiety is a major determinant of the small intestinal uptake and subsequent biliary excretion of. Methods to evaluate biliary excretion of drugs in humans. Thehighest rate of biliary excretion wasthat ofpaminobenzylpenicillin over 20% of the dose in 2. Some interacting drugs, such as cyclosporine, inhibit multiple sites of statin disposition table 1,3 resulting in larger increases in serum concentrations and subsequent risk for myopathy. Inhibition of biliary phospholipid and cholesterol secretion.
Pdf biliary excretion of ciprofloxacin and piperacillin. A number of organic anions selectively inhibit the biliary secretion of cholesterol and phospholipids without affecting bile acid secretion. Influence of taurocholate on hepatic clearance and biliary. After administration of cpt11, a camptothecin derivative exhibiting a wide spectrum of antitumor activity, doselimiting gastrointestinal toxicity with great interpatient variability is observed. Inhibition of intestinal cholesterol absorption by. The best result was obtained from a simple regression tree that used predicted oatp1b1 percentage inhibition at the root node of the tree. It was hypothesized that inhibition of mrp2mediated ag transport by pb or pb metabolites, and pb induction of mrp3, may contribute to the. Increased lysosomal discharge into bile was excluded as a potential contributor to increased biliary lipid. We studied the effect of cefmetazole, a thirdgeneration cephalosporin, on biliary lipid secretion in the rat. Biliary excretion of irinotecan and its metabolites. The type of sugar moiety is a major determinant of the. Biliary excretion an overview sciencedirect topics. Intravenous injection of piperacillin at doses ranging from 0. Effects of administration of hydrocortisone on the renal.
Previous studies have demonstrated that phenobarbital pb significantly impairs the biliary excretion of acetaminophen glucuronide ag in rats. The effects of adding verapamil 240 mgday on steadystate plasma concentrations of digoxin were studied. Biliary excretion is an important route of elimination and may cause. Inhibitory action of cyclobutyrol on the secretion of biliary cholesterol and phospholipids. That is, both hepatic uptake clearance, assessed in integration plot analysis, and steadystate biliary clearance defined with respect to he. The inhibition of biliary excretion of methotrexate by probenecid was also predicted from in vitro interaction based on isolated rat hepatocytes ueda et al. Labeling example eltrombopag drug interactions section 7. Here, we show that myrcludex bmediated ntcp inhibition actually causes an increase in biliary cholesterol and phospholipid excretion whereas biliary bile salt output and bile salt composition remains unchanged. Collado, alejandro esteller and ja vier gonzalez department of physiology and pharmacology, university of salamanca and department of.
Oct 27, 2004 a sigmoidal inhibition model was fit to the taurocholate biliary excretion indexxenobiotic concentration data to estimate the ic 50 of xenobiotics for biliary excretion of taurocholate. Pergamon press pic impairment of sulfobromophthalein biliary excretion and inhibition of glutathione 5transferase activity induced by perhexiline maleate in rats maria a. Biliary excretion involves active secretion of drug molecules or their metabolites from hepatocytes into the bile. Induction and inhibition metabolism based drugdrug and other interactions can have a significant influence on the use and safety of many drugs.
Inhibition of biliary excretion of methotrexate by probenecid in rats. The results suggest that inhibition of hepatobiliary transport is a likely mechanism for the interaction between erythromycin and ximelagatran. After oral feeding 100 mgkg and iv infusion 5 mgkgh of camostat mesilate, the original compound and both metabolites appeared in bile, but could not be detected in. Several preclinical tools involving in vivo or ex vivo rodent models can be utilized to evaluate the extent of biliary excretion of drugs and the interaction of xenobiotics with bile salt transport proteins. T1 inhibition by bromsulphthalein of the biliary excretion of its glutathione conjugate. To determine the site of this inhibition and gain insight into its mechanism, normal, spraguedawley and homozygous gunn rats were infumsed with unconjugated bilirubin and a watersoluble model conjugate, bilirubin ditaurate. Previous observations indicated a depressed ndemethylation and biliary excretion of dab after glutathione depletion. Inhibition of biliary excretion drug interactions in biliary excretion. Biliary excretion definition of biliary excretion by. The oral bioavailability, excretion and cytochrome p450.
Thus, probenecid may be a candidate which can be used clinically to inhibit the biliary excretion of cpt11 metabolites, whereas an interaction between most of the other compounds and mrp2 is more unlikely. Inhibition by bromsulphthalein of the biliary excretion of. In addition, in rats, biliary excretion is the major elimination pathway for methotrexate, and 72% of an intravenous dose was recovered in the bile masuda et al. Therefore, to further validate the influence of cbs on their transport function, we observed the biliary excretion and cumulative biliary excretion of baicalin and mitoxantrone, respectively, finding that the transport activities of mrp2 and bcrp were obviously enhanced by cbs in a dosedependent manner. In vitro studies demonstrate that eltrombopag is an inhibitor of the. Carriermediated mechanism for the biliary excretion of. Efficacy, tissue distribution and biliary excretion of methyl e3,5dihydroxy9,9diphenyl6, 8nonadienoate cp83101, a hepatoselective inhibitor of hmgcoa reductase activity in the rat. Harvardmit division of health sciences and technology hst. Inhibition of the efflux transporters may affect the pharmacokinetics of tnp and result in a drugdrug interaction between tnp and the concomitant transporter inhibitor or inducer in clinic. Transportermediated secretion of a drug into the bile may be competitively inhibited by other drugs or endogenous substances. Inhibition of biliary cholesterol and phospholipid secretion during cyclobutyrolinduced hydrocholeresis. Three inhibitors probenecid, sulfobromophthalein and glycyrrhizin were also found to inhibit the biliary excretion of sn38 and sn38glu in rats in vivo, and the degrees of inhibition were compatible with the estimated values based on the ratios of ki and unbound concentrations in circulating plasma. The biliary excretion of the parent drug in ehbr was 38% of that in normal rats, whereas the 3glucuronide, a main metabolite of gpfx, was scarcely excreted into the bile in ehbr.
The inhibition of icg excretion was completely prevented by subsequent administration of dithiothreitol 0. This may not be the complete list of references from this article. Intestinal heme oxygenase inhibition and increased biliary iron excretion by metalloporphyrins george s. Furthermore, the study demonstrated the value of direct bile sampling in humans for the identification of primary biliary metabolites. Inhibition of the efflux transporters may affect the pharmacokinetics of tnp and result in a drugdrug interaction between tnp and the concomitant transporter inhibitor. Therefore, this interaction may be a useful model in rats. Inhibition of human hepatic bile acid transporters by. Frontiers inhibition of pglycoprotein and multidrug.
Learn vocabulary, terms, and more with flashcards, games, and other study tools. Inhibition of biliary cholesterol and phospholipid. Studies also suggested that mrp2 mediates ag biliary excretion, and mrp3 is involved in ag basolateral export. Reduced gastrointestinal toxicity following inhibition of. Hepatic processing of transforming growth factor beta in the rat. In addition to transport and metabolism processes, which. These studies lead to the conclusion that ndemethylation is the major ratedetermining factor for biliary excretion. Inhibition of biliary excretion of methotrexate by probenecid. Impairment of sulfobromophthalein biliary excretion and. Biliary excretion gregus 1987 the journal of clinical. Importance of hepatic transporters in clinical disposition of drugs. Intracellular drug concentrations and transporters in the. As noted at the outset of this article, the purpose of the current investigation was to test the hypothesis that inhibition of human hepatic bile acid transporters by tolvaptan and metabolites could play a role in tolvaptanassociated dili.
The mechanism of biliary excretion of methyl mercury. In such conditions, clearance of the drug may be reduced and the dosage regimen must be adapted. Inhibition of biliary excretion of indocyanine green by. These proteins are members of the abc family of transporters table 9. The excretion of piperacillin sodium in bile was studied after intravenous injection of 2 g n 5 and 4 g n 7. Reduced gastrointestinal toxicity following inhibition of the biliary excretion of irinotecan and its metabolites by probenecid in rats article in pharmaceutical research 199. For a series of renin inhibitors, mw correlates highly r2 0. Opiates increase duodenal muscle tone and inhibitpropulsivemotoractivity. This marker is excreted in half an hour in intestine at normal hepatic functioning. The potential for an interaction between mrp2 abcc2 and.
Rosenberg, and attallah kappas rockefeller university hospital, new york, new york the effects of synthetic metalloporphyrins on heme oxygenase activity in the epithelium of the proxi. However, advances in technology over the past decade have allowed alternative methods to be employed to obtain both clinical adme and pharmacokinetic pk information. Induction of drug metabolism can lead to unexpected drops in drug concentration or the buildup of metabolites. An in vitro methods of characterizing biliary excretion of a chemical entity using a single hepatocyte culture. Effects of colchicine on the maximum biliary excretion of. Harvardmit division of health sciences and technology 151. A similar biliary output in rat has been reported for alpase 18. Induction and inhibition of the metabolism and biliary. This means the inhibitor has no impact on the metabolism of the drug because the aucs are equal, and therefore, the enzyme being tested does. Pdf efficacy, tissue distribution and biliary excretion.
Inhibition of biliary phospholipid and cholesterol secretion by bilirubin in the spraguedawley and gunn rat. May 28, 2019 the higher rate of biliary cholesterol excretion after ntcp inhibition was not accompanied by changes in biliary bile salt secretion p biliary excretion of glycinecholic acid gca as a percentage of total gca accumulation was reduced in schh treated with either csa or trog. Request pdf reduced gastrointestinal toxicity following inhibition of the biliary excretion of irinotecan and its metabolites by probenecid in rats to ameliorate the lateonset of severe. Department of pharmacology, toxicology and therapeutics, university of kansas medical center, kansas city, kansas. Human absorption, distribution, metabolism and excretion. Reduced gastrointestinal toxicity following inhibition of the. Its purpose is to provide for drainage of bile past obstructed bile ducts and into the small intestine, where it aids.
In parallel, the biliary clearance was moderately reduced. The results of studies focused on these alternative mechanisms will be reported subsequently. Biliary excretion of ximelagatran and its metabolites and. Inhibition of biliary excretion is typically not apparent at the level of. This inhibition by probenecid was confirmed in vivo both in the uptake and excretion processes of methotrexate across sinusoidal and canalicular membranes, respectively. Inhibition of biliary excretion of methotrexate by. Biliary excretion of ciprofloxacin and piperacillin was determined in cholestatic patients who had undergone endoscopic cholangiography.
Methods used to determine in vivo biliary clearance. Cyclosporine is an inhibitor of oatp1b1, oatp1b3, pgp, and adenosine triphosphate. The results, therefore, suggest that the biliary excretion of icg was inhibited by secondary changes in the redox status of thiols in hepatocytes caused by a transient increase in oxidized glutathione. Delay in its excretion indicates hepatic and biliary mal function. May 01, 1991 monte mj, cava f, esteller a, jimenez r. Probably some endocytic vesi cles escape from fusion with the lysosomes and associate with the bile canalicular membrane, result. The interaction between methotrexate and probenecid was. Inhibition of intestinal cholesterol absorption by ezetimibe. The spectrum of inhibition of biliary excretion by chlordecone and mirex were similar in that morphine. The oral bioavailability, excretion and cytochrome p450 inhibition properties of epiberberine. Systemically available linagliptin was mainly excreted unchanged via bile 49% of i. M was a much more potent inhibitor of taurocholate biliary excretion than bosentan ic 50 31 11.
Choleresis and inhibition of biliary lipid secretion. Comparison of the inhibition of biliary excretion produced by certain. The effects of the administration piperacillin on bile flow and biliary lipid secretion were studied in male wistar rats. Coadministration of probenecid reduced the biliary clearance of methotrexate in a dosedependent manner in rats. Induction and inhibition of drug metabolism inhibition of biliary exc. Comprising providing cell culture comprising hepatocytes forming at least one bile canaliculus. Methods of drug interaction studies this document is an informal. We describe the use of a commercially available high content cell imaging algorithm cellomics arrayscan spot detector to quantify biliary excretion of the fluorescent probe substrate cholylllysylfluorescein clf from rat hepatocytes cultured in collagenmatrigel sandwich configuration and to explore inhibition of this process by a variety of test compounds. Bilirubin is one of several organic anions that selectively inhibit the biliary secretion of phospholipid and cholesterol without affecting bile salt secretion.
Inhibition by bromsulphthalein of the biliary excretion of its glutathione conjugate. Thus, direct excretion of linagliptin into the gut may be an alternative excretion route in the presence of liver and renal impairment. In dogs receiving creatinine, taurocholate, and ampicillin without infusion of hydrocortisone, mean concentration of ampicillin in serum, minute biliary weight, and renal clearance rate of ampicillin remained constant throughout the 150 min of study, while mean biliary concentration of ampicillin and rate of excretion decreased during the last. Inhibition of biliary cholesterol and phospholipid secretion. Excretion of the dipeptidyl peptidase4 inhibitor linagliptin. Methods to evaluate biliary excretion of drugs in humans ncbi. The predicted degrees of inhibition by most compounds were minimal whereas approximately 75% inhibition was predicted for probenecid. Induction and inhibition of drug metabolism inhibition of biliary excretion by nagaraju b 2. The interaction between methotrexate and probenecid was examined as an interaction model since this interaction has already been clinically reported. Inhibition of biliary excretion the interaction between digoxin and verapamil was studied in six patients mean age 61 5 years with chronic atrial fibrillation. Biliary excretion of piperacillin e w taylor, v poxon, j. Effects of probenecid, an inhibitor of mrp2abcc2, on the biliary excretion and mucosal intestinal tissue concentration of cpt11 and its metabolites were examined in rats. Carriermediated mechanism for the biliary excretion of the. Mar 19, 2014 induction and inhibition of drug metabolism inhibition of biliary excretion by nagaraju b 2.
Colchicine, an inhibitor of intracellular vesicular transport, has been reported to inhibit the biliary excretion of bile acids and organic anions, but the previous findings are. The in vivo inhibition constants of rifampicin used as initial input parameters for oatp1bs k i,u,oatp1bs and multidrug resistance. The hepatic metabolism and biliary and pancreatic excretion of the serine protease inhibitor camostat mesilate and its metabolitesfoy251 and gba were studied in rats in vivo and inin situ liverperfusion experiments. To ameliorate the lateonset of severe gastrointestinal toxicity provoked by irinotecan cpt11, which may be related to the biliary excretion of cpt11 andor its metabolites. Rosenberg, and attallah kappas rockefeller university hospital, new york, new york the effects of synthetic metalloporphyrins on heme oxygenase activity in. Enzyme inhibitor an enzyme inhibitor is a compound that decreases or diminish the rate or velocity of an enzymecatalyzed reaction by influencing the binding of s and or its turnover number. To clarify the biliary excretion mechanism of gpfx, studies of uptake. Other factors the efficacy of drug excretion by biliary system can be tested by an agent i. Hepatic and pancreatic metabolism and biliary excretion of. R j coffey, jr, l j kost, r m lyons, h l moses, and n f larusso. To clarify the biliary excretion mechanism of gpfx, studies of uptake by bile canalicular membrane vesicle cmv were performed. Effect of oatpbinding on the prediction of biliary excretion.
The biliary excretion profiles for both the lactone and carboxylate forms of cpt11 and its metabolites were determined. Inhibition of pglycoprotein and multidrug resistance. Inhibition of mast cellsecreted histamine decreases biliary proliferation and fibrosis in primary sclerosing cholangitis mdr222 mice hannah jones,1 laura hargrove,1 lindsey kennedy,2,3 fanyin meng, allyson grafeaton,2 jennifer owens,2 gianfranco alpini,2,3 christopher johnson,3 francesca bernuzzi,4 jennifer demieville,2 sharon demorrow,2,3 pietro invernizzi,4 and heather francis. These results indicated the important roles of pgp and mrp2 in hepatobiliary excretion and plasma exposure of tnp and tnpg. Quantification of druginduced inhibition of canalicular. Excretion of sulfhydryl in bile was not influenced by s. The results indicated that incorporation of predicted oatp inhibition improves accuracy of biliary excretion models.
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