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1.
1-Nitropyrene (1-NP), present in diesel engine emissions, is a potent mutagen to bacteria, such as those found in mammalian intestinal tract, which contain nitroreductase enzymes. The purposes of this study were to determine the importance of bile as a route of excretion of 1-NP metabolites and to determine if reabsorption of biliary metabolites required the presence of intestinal bacteria. The bile ducts of male Fischer-344 rats were cannulated, 0.3 or 1.2 mumoles [3H]1-NP was given i.v., and bile, urine, and feces were collected for 24 hr. Biliary excretion accounted for 70 (80%) or 170 (60%) nmoles of [3H]1-NP after the low and high dose, respectively, with half-times for excretion of 1.7 hr +/- 0.3 (+/- S.E.M.) and 3.4 hr +/- 1.6 (+/- S.E.M.). Excretion of [3H]1-NP equivalents in the urine was linearly related to dose, with 6 or 16 nmoles (8%) excreted in 24 hr. At the low dose, more radioactivity appeared in the urine in control rats compared to bile-duct cannulated rats, suggesting that reabsorption of 1-NP metabolites occurred. Pretreatment of rats with orally administered antibiotics prior to i.v. injection of 0.3 mumole [3H]1-NP decreased radioactivity excreted in urine compared to untreated controls, suggesting that intestinal microorganisms may alter the biliary metabolites of 1-NP to facilitate reabsorption. Pretreatment of rats with buthionine sulfoximine, a glutathione depletor, decreased the excretion of certain biliary metabolites, suggesting that they were mercapturic acids of 1-NP metabolites. In summary, the results of these studies indicate that bile was an important route of excretion of nitropyrene metabolites. A portion of the excreted metabolites was reabsorbed from the gut, and this reabsorption required the presence of gut microorganisms.  相似文献   

2.
Isolated perfused rat liver preparations were utilized to study the drug-induced modification of biliary excretion of [14C]4-chlorobiphenyl (1-CB) and [14C]2,4,5-2′,4′,5′-hexachlorobiphenyl (6-CB) and their metabolites. The effect of pretreatment of rats with mirex was compared with that of phenobarbital (PB) and 6-CB by measuring the biliary excretion of 1-CB and the pharmacokinetics of 1-CB and its metabolites in the perfusate of liver preparations obtained from control and treated rats. The biliary excretion of 1-CB metabolites by mirex-pretreated livers was suppressed by 92% of that in control livers. The rate of metabolism of 1-CB by mirexpretreated livers was slightly decreased. However, the suppression of biliary excretion of 1-CB metabolites does not appear to be related either to decreased rate of metabolism or to the rate of bile flow. These conclusions are borne out from the following two observations: first, the metabolites of 1-CB accumulate at increasing concentrations in the perfusate of mirexpretreated livers; secondly, mirex-pretreated livers had elevated bile flows. Biliary excretion of exogenously added metabolites of 1-CB by mirextreated livers was suppressed by 85% of that of control livers. PB and 6-CB pretreatment caused a statistically significant increase in the biliary excretion of 1-CB metabolites. This was accompanied by a slight but statistically nonsignificant increase in the rate of bile flow. Biliary excretion of 6-CB was completely suppressed by mirex pretreatment and was unaffected by PB. These results indicate that while PB-induced modification of biliary excretion of PCBs may be associated with their metabolism, mirex-induced suppression is associated with the transport of otherwise readily excretable metabolites from the hepatocytes into the bile canaliculi.  相似文献   

3.
The role of Mrp2, Bcrp, and P-glycoprotein in the biliary excretion of acetaminophen sulfate (AS) and glucuronide (AG), 4-methylumbelliferyl sulfate (4MUS) and glucuronide (4MUG), and harmol sulfate (HS) and glucuronide (HG) was studied in Abcc2(-/-), Abcg2(-/-), and Abcb1a(-/-)/Abcb1b(-/-) mouse livers perfused with the respective parent compounds using a cassette dosing approach. Biliary clearance of the sulfate conjugates was significantly decreased in Bcrp-deficient mouse livers, resulting in negligible biliary excretion of AS, 4MUS, and HS. It is noteworthy that the most profound decrease in the biliary clearance of the glucuronide conjugates was observed in Bcrp-deficient mouse livers, although the biliary clearance of 4MUG was also approximately 35% lower in Mrp2-deficient mouse livers. As expected, biliary excretion of conjugates was not impaired in P-glycoprotein-deficient livers. An appreciable increase in perfusate recovery due to a shift in the directionality of metabolite excretion, from bile to perfusate, was noted in knockout mice only for conjugates whose biliary clearance constituted an appreciable (> or =37%) fraction of total hepatic excretory clearance (i.e., 4MUS, HG, and HS). Biliary clearance of AG, AS, and 4MUG constituted a small fraction of total hepatic excretory clearance, so an appreciable increase in perfusate recovery of these metabolites was not observed in knockout mice despite markedly decreased biliary excretion. Unlike in rats, where sulfate and glucuronide conjugates were excreted into bile predominantly by Mrp2, mouse Bcrp mediated the biliary excretion of sulfate metabolites and also played a major role in the biliary excretion of the glucuronide metabolites, with some minor contribution from mouse Mrp2.  相似文献   

4.
The metabolism of allylisopropylacetamide (AIA) was studied in normal and phenobarbitone (PB)-pretreated intact male rats and in rats with biliary fistula. Because of the side effects of AIA in the intact rat, the hepatic metabolism of AIA was further investigated in the isolated rat liver perfused with defibrinated rat blood firstly, to confirm the in vivo results and secondly, to further characterize some of the processes involved in the biliary excretion of drugs.At least four days were required to eliminate a single porphyrinogenic dose of 400 mg [2-14C] AIA per kg body wt from the intact rat, 70 per cent of the administered radioactivity appeared in the urine, as AIA and three metabolites A, B, and C, and 10 per cent in the faeces. AIA, 2-isopropyl-4,5-dihydroxypentanamide (AIA-glycol) and 2-isopropyl-4,5-dihydroxypentanoic acid-γ-lactone (AIA-lactone) were identified in either extracts of glucuronidase-sulphatase-hydrolysed urine. AIA and two other metabolites, D and E, were excreted in bile. The metabolism of AIA by the perfused liver appeared quantitatively similar to that in fistula rats judged by the biliary excretion and by the decline in microsomal cytochrome P-450 after AIA. PB-pretreatment of the rats increased the per cent dose excreted per hour in the bile 2 to 3-fold, enhancing the initial excretion rate of metabolite D from 4 to 5-fold and that of AIA almost 2-fold.The decrease of microsomal P-450 after AIA administration to PB-pretreated rats, previously considered to be biphasic, has been shown to have an additional component with half-life of 4 min. The rapid decline in hepatic P-450 after AIA in PB-pretreated rats correlated with an increased biliary excretion of one particular metabolite of AIA. A pharmacokinetic analysis of the biliary excretion data based on a two-compartment model shows that the rate-limiting step in the biliary excretion of both AIA and metabolite D can be adequately represented as a first-order linear reaction.  相似文献   

5.
DPC 333 [(2R)-2-{(3R)-3-amino-3-[4-(2-methylquinolin-4-ylmethoxy)phenyl]-2-oxopyrrolidin-1-yl}-N-hydroxy-4-methylpentanamide] is a potent human tumor necrosis factor alpha-converting enzyme inhibitor with potential therapeutic implications for rheumatoid arthritis. Methotrexate (MTX), a drug for the treatment of rheumatoid arthritis, is eliminated primarily unchanged via renal and biliary excretion in humans as well as in rats and dogs. The objective of the present study was to investigate the potential effect of DPC 333 on the disposition of MTX. In dogs, DPC 333 administered orally at 1.7 mg/kg 15 min before the intravenous administration of [14C]MTX (0.5 mg/kg) did not alter the plasma concentration-time profile of MTX; however, the total amount of radioactivity excreted in urine increased from 58.7% to 92.2% of the dose, and the renal clearance increased from 1.8 ml/min/kg to 2.9 ml/min/kg, suggesting a decrease in MTX disposition via biliary excretion. The biliary excretion of MTX was investigated in isolated perfused livers prepared from wild-type and TR(-) [multidrug resistance-associated protein 2 (Mrp2)-deficient] Wistar rats in the absence and presence of DPC 333. Mrp2-mediated biliary excretion of MTX was confirmed with 95.8% and 5.1% of MTX recovered in the bile of wild-type and TR(-) Wistar rats, respectively. DPC 333 at an initial perfusate concentration of 50 microM completely blocked the biliary excretion of MTX, but not the clearance from perfusate, in both wild-type and TR(-) rats. These results suggest that the enhanced renal elimination of MTX may be due to the potent inhibition of biliary excretion and active renal reabsorption by DPC 333 and/or its metabolites.  相似文献   

6.
Technical grade dinitrotoluene (DNT) is hepatocarcinogenic when fed to rats. DNT is oxidatively metabolized by hepatic enzymes and reductively metabolized by rat intestinal microflora in vitro. The objectives of the present studies were to determine the importance of bile as a route of excretion for DNT metabolites and to investigate the role of enterohepatic circulation in the metabolism of DNT. The common bile ducts of male and female F-344 rats were cannulated with an uninterrupted cannula at the hepatic and ileal ends. After 24 hr, male rats were given a po dose of 35, 63, or 100 mg 2,4-[14C]DNT/kg; female rats received 35 mg 2,4-[14C]DNT/kg. Immediately prior to dosing, the cannula was snipped and bile was allowed to collect in a glass reservoir, surgically implanted in the peritoneal cavity, which could be sampled externally. In males, excretion of 14C in bile was linearly related to dose. From 9.2 to 29.2 μmol eq of [14C]DNT (approximately 25% of the dose) appeared in bile within 24 hr. Females dosed with 35 mg/kg excreted only 18% of the dose in the bile. Over 90% of the radioactivity in the bile was the glucuronide conjugate of 2,4-dinitrobenzyl alcohol (DNBAlc-G). In comparison to control rats, in which bile flow to the small intestine was uninterrupted, collection of bile decreased the amount of 14C excreted in urine. In both males and females most of the 2,4-DNT dose excreted in the urine was in the form of the oxidized metabolites DNBAlc-G and 2,4-dinitrobenzoic acid. These results indicate that bile is an important route of excretion for 2,4-DNT metabolites and that metabolites excreted in the bile can be reabsorbed from the gut.  相似文献   

7.
Metabolism and excretion of atorvastatin in rats and dogs.   总被引:1,自引:0,他引:1  
Atorvastatin (AT) is a second-generation potent inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase, clinically approved for lowering plasma cholesterol. Using a mixture of [D(5)/D(0)] AT and/or [(14)C]AT, the metabolic fate and excretion of AT were examined in rats and dogs following single and multiple oral doses. Limited biliary recycling was examined in one dog after a single dose of AT. AT-derived metabolites in bile samples were identified by metabolite screening of the [D(5)/D(0)] AT molecular clusters using tandem mass spectrometry. Bile was a major route of [(14)C] drug-derived excretion, accounting for 73 and 33% of the oral dose in the rat and dog, respectively. The remaining radioactivity was recovered in the feces; only trace amounts were excreted in urine. Radioactive components identified in rat and dog bile were the para- and ortho-hydroxy metabolites, a glucuronide conjugate of ortho-hydroxy AT, and unchanged AT. Two minor radioactive components were identified as beta-oxidation products of AT with one confirmed as a beta-oxidized AT derivative. The reappearance of AT and major metabolites in bile from a dog administered a sample of its previously excreted bile indicated biliary recycling is an important component in AT metabolism. Multiple dose administration in rats did not alter biliary metabolic profiles. Rat and dog plasma profiles after multiple dose administration were similar and showed no additional metabolites not found in bile. Examination of rat and dog bile and plasma indicates that AT primarily undergoes oxidative metabolism.  相似文献   

8.
Germfree (GF) rats and antibiotic-treated rats with cannulated bile ducts (ABC) were given single oral doses of 2-(S-(N-[2H3]acetyl)cysteine)-N-isopropyl[1-14C]acetanilide. The GF rats excreted the dose in about equal quantities in the urine and feces; and the ABC rats excreted the dose in about equal quantities in the urine, feces, and bile. The mercapturate (60-75% of the dose in both cases) was isolated and the amount of exchange of N-acetyl deuterium to N-acetyl hydrogen was determined for all samples by mass spectrometry. The percentages of exchange were: ABC rats, bile 6.5%, urine 13%, feces 0.0%; GF rats, urine 15%, feces 4.7%. The remainder of the doses was present as the mercapturic acid sulfoxide. ABC rats dosed with 2-(S-[3,3-3H]cysteine)-N-isopropyl[1-14C]acetanilide (14C/3H = 0.50) excreted 42% of the dose in the urine and bile as the mercapturic acid that had a 14C/3H ratio the same as the original cysteine conjugate. The results of these studies show that a mercapturic acid and a cysteine conjugate can be absorbed from the gastrointestinal tract and resecreted in the bile or excreted by the kidney without having undergone metabolism other than acetylation of the cysteine nitrogen atom and oxidation of the sulfur to a sulfoxide. ABC rats were also dosed with 2-methylthio-N-isopropyl[1-14C]acetanilide, a suspected metabolic intermediate in the metabolism of propachlor (2-chloro-N-isopropylacetanilide). The dose was excreted in about equal quantities in the bile (48%) and urine (46%) as metabolites with a methylsulfonyl group in the 2-position. All are known metabolites of propachlor in conventional rats.  相似文献   

9.
The induction of an experimental hepatitis did not affect the overall ability of the rat to metabolize the flavanol 3-O-(+)-[14C]methylcatechin by methylation or glucuronidation. The induction of hepatitis did cause a significant increase in metabolite excretion in urine (from 52% of the dose in control rats to 88% in hepatitis). Fecal excretion was correspondingly depressed (44 to 4% of the dose). In bile duct-cannulated rats, the induction of hepatitis prior to 3-O-(+)-[14C]methylcatechin administration resulted in low 14C excretion (38%) in bile (cf. 58% in bile of controls). The data obtained indicate that following induction of hepatitis biliary metabolites reabsorbed from the intestine are not reexcreted in bile in an enterohepatic cycle as in the normal rat but are excreted via the kidney. Induction of hepatitis did not affect the fast clearance of unchanged 3-O-methyl-(+)-catechin from plasma but plasma clearance of the metabolites was reduced from 112 to 89 ml/hr.  相似文献   

10.
The mechanism for the vasopressin- and epinephrine-induced decrease in bile formation and increase in sinusoidal efflux of glutathione was investigated in rat livers perfused with recirculating fluorocarbon emulsion. Vasopressin and epinephrine transiently decreased bile flow and excretion of endogenous bile acids and glutathione and increased the bile/perfusate ratio of [14C]sucrose, suggesting an increase in junctional permeability, but had no effect on the bile/perfusate ratio of [3H]polyethylene glycol-900. The decreased biliary glutathione was balanced by an increase in sinusoidal efflux, such that total hepatic release remained unchanged. The adrenergic antagonist dihydroergotamine blocked the effects of epinephrine. To examine whether an increase in junctional permeability per se could account for the changes in glutathione efflux, biliary permeability was increased by either bile duct ligation, lowering of perfusate Ca2+ concentration with ethylene glycol bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA), or addition of taurolithocholate, a cholestatic bile acid. All three maneuvers produced a decrease in biliary glutathione excretion and a concomitant increase in sinusoidal glutathione efflux, whereas total glutathione release was largely unaffected. The effects of EGTA were partially reversed if CaCl2 was reintroduced into the perfusate. Because the GSH/GSSG ratio in perfusate could not be measured in this experimental system due to the spontaneous oxidation of GSH to GSSG, additional experiments in the nonrecirculating mode examined the effects of vasopressin and bile duct ligation on sinusoidal release of GSH and GSSG. In control livers there was no detectable GSSG in perfusate (less than 0.5 nmol.min-1.g-1). After vasopressin administration, the additional sinusoidal glutathione was mainly as GSH, although there was also a significant amount of GSSG (1-2 nmol.min-1.g-1). The additional glutathione released into perfusate after bile duct ligation was 47% as GSSG. When vasopressin was administered to livers whose bile duct had been ligated, its ability to enhance sinusoidal glutathione release was diminished, suggesting that the effects of vasopressin and bile duct ligation are not additive. These observations support previous findings that vasopressin and epinephrine can modulate hepatocyte tight junctional permeability and demonstrate that these hormones produce cholestasis and inverse changes in sinusoidal and biliary glutathione efflux. Other maneuvers that increased biliary permeability to [14C]sucrose also produced cholestasis and a redistribution of glutathione efflux from bile to perfusate, suggesting that an increase in junctional permeability may allow biliary glutathione to reflux from bile to plasma.  相似文献   

11.
Methadone, administered subcutaneously to rats once daily for 12 days, nearly doubled the bile flow rate in isolated perfused livers. The increase in bile flow was accompanied by an increase in the biliary excretion rate of metabolites of 3H-methadone, which was added to the perfusion system at a dose of 1 mg/kg body weight. To determine whether an alteration of the rate of methadone metabolism accounted for this effect, Phenol-3,6-dibromphthalein disulfonate (DBSP), an analogue of BSP which is excreted unchanged in the bile, was added (80 mg/kg) to the perfusion system. It was also excreted at an enhanced rate by the livers of the methadone pretreated rats. Neither the plasma disappearance rate of methadone or DBSP nor the pattern of biotransformation of methadone was significantly affected by the methadone pretreatment. It is concluded that chronic methadone treatment of rats stimulates bile flow via an unknown mechanism, resulting in increased biliary excretion of methadone metabolites and possibly of other compounds which undergo elimination in the bile.  相似文献   

12.
Previous reports have demonstrated that sulfate metabolites may be excreted into bile by the multidrug resistance-associated protein 2 (Mrp2, Abcc2). Although recombinant human breast cancer resistance protein (BCRP, ABCG2) has affinity for sulfated xenobiotics and endobiotics, its relative importance in biliary excretion of sulfate metabolites in the intact liver is unknown. In the present studies, the potential contribution of Bcrp1 to the biliary excretion of acetaminophen sulfate (AS) was examined following acetaminophen administration (66 micromol, bolus) to isolated perfused livers (IPLs) from wild-type Wistar and Mrp2-deficient (TR(-)) Wistar rats in the presence or absence of the Bcrp1 and P-glycoprotein inhibitor, GF120918 [N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide]. Recovery of AS in bile of TR(-) rat livers was approximately 5-fold lower relative to wild-type controls (0.3 +/- 0.1 versus 1.5 +/- 0.3 micromol). In the presence of GF120918, biliary excretion of AS was decreased approximately 2-fold in both TR(-) (0.16 +/- 0.09 micromol) and wild-type (0.8 +/- 0.3 micromol) rat IPLs. These changes were primarily due to alterations in the rate constant governing biliary excretion of AS, which was decreased approximately 90% in TR(-) relative to wild-type rat IPLs (0.02 +/- 0.01 versus 0.2 +/- 0.1 h(-1)) and was further decreased in the presence of GF120918 (0.010 +/- 0.003 and 0.12 +/- 0.05 h(-1); TR(-) and wild-type, respectively). In vitro assays indicated that impaired AS biliary excretion in the presence of GF120918 was due to inhibition of Bcrp1, and not P-glycoprotein. In conclusion, Mrp2 and, to a lesser extent, Bcrp1 mediate biliary excretion of AS in the intact liver.  相似文献   

13.
Methyl bromide is used as a disinfectant to fumigate soil and a wide range of stored food commodities in warehouses and mills. Human exposure occurs during the manufacture and use of the chemical. The purpose of this investigation was to determine the disposition and metabolism of [14C]methyl bromide in rats after inhalation. Male Fischer-344 rats were exposed nose only to a vapor concentration of 337 nmol [14C]methyl bromide/liter air (9.0 ppm, 25 degrees C, 620 torr) for 6 hr. Urine, feces, expired air, and tissues were collected for up to 65 hr after exposure. Elimination of 14C as 14CO2 was the major route of excretion with about 47% (3900 nmol/rat) of the total [14C]methyl bromide absorbed excreted by this route. CO2 excretion exhibited a biphasic elimination pattern with 85% of the 14CO2 being excreted with a half-time of 3.9 +/- 0.1 hr (means +/- SE) and 15% excreted with a half-time of 11.4 +/- 0.2 hr. Half-times for elimination of 14C in urine and feces were 9.6 +/- 0.1 and 16.1 +/- 0.1 hr, respectively. By 65 hr after exposure, about 75% of the initial radioactivity had been excreted with 25% remaining in the body. Radioactivity was widely distributed in tissues immediately following exposure with lung (250 nmol equivalents/g), adrenal (240 nmol equivalents/g), kidney (180 nmol equivalents/g), liver (130 nmol equivalents/g), and nasal turbinates (110 nmol equivalents/g) containing the highest concentrations of 14C. Radioactivity in livers immediately after exposure accounted for about 17% of the absorbed methyl bromide. Radioactivity in all other tissues examined accounted for about 10% of the absorbed methyl bromide. Elimination half-times of 14C from tissues were on the order of 1.5 to 8 hr. In all tissues examined, over 90% of the 14C in the tissues was methyl bromide metabolites. The data from this study indicate that after inhalation methyl bromide is rapidly metabolized in tissues and readily excreted.  相似文献   

14.
The biliary excretion of radioactivity by adult Wistar rats given i.v. 7-methyl-[7-14C]benz[c]acridine(14C-7-MBAC) and [methyl-3H]-7-methylbenz[c]acridine (3H-7-MBAC) (2 mg/kg) was 61% and 48%, respectively, in males in six hours. Females excreted 33% of a 2 mg/kg dose of 3H-7-MBAC in the same time-period. For male rats, the urinary and faecal excretions were about 10% and 61% of the dose of 14C-7-MBAC, respectively, in seven days. No enterohepatic circulation could be demonstrated in control male rats. The biliary excretion of radioactivity by phenobarbital- and 3-methylcholanthrene-induced male rats given 14C-7-MBAC was similar to or greater than that of control male rats. The organo-soluble biliary metabolites after beta-glucuronidase/arylsulphatase hydrolysis were separated by h.p.l.c., and quantitative metabolite distributions were obtained for induced and control rats by comparison with metabolite standards. The mutagenicity of bile from carcinogen-dosed control rats was greater than that of equivalent bile from carcinogen-dosed 3-methylcholanthrene-pretreated animals.  相似文献   

15.
The purpose of this study was to determine how prior exposure of rats to graded concentrations of diesel exhaust would affect respiratory tract tissue metabolism of 1-nitropyrene (NP), a known constituent of diesel exhaust. Rats were exposed (whole body) 7 hr/day, 5 days/week for 4 weeks to clean air (controls) or to diluted diesel exhaust containing concentrations of 350, 3300, and 7400 micrograms particles/m3. After exposures, nasal tissue and lungs from rats were tested for their ability to metabolize NP. Rat nasal tissue was incubated for 10 min with 20 microM 1-[14C]NP. Isolated perfused rat lungs were perfused for 90 min with 25 microM 1-[14C]NP. NP metabolites formed in rat nasal tissue and the isolated perfused rat lung were separated by high-pressure liquid chromatography. Exposure of rats to 7400 micrograms particles/m3 for 4 weeks resulted in significant increases (twofold) in rates of NP metabolism in both nasal tissue (440 pmol/mg protein/min) and the isolated perfused rat lung (112 nmol/g lung). Exposure of rats to lower concentrations of diesel exhaust did not increase the rates of NP metabolism in either rat nasal tissue or perfused rat lungs. In all cases, the major metabolites of NP formed in nasal tissue and perfused lungs were 3-, 6-, and 8-hydroxy-1-nitropyrene and 4,5-dihydro-4,5-dihydroxy-1-nitropyrene. A fourfold increase was observed in the amounts of 14C covalently bound in lungs from rats exposed to 7400 micrograms particles/m3. The results from this study indicate that exposure to diesel exhaust particles significantly alters metabolism and subsequent covalent binding of NP.  相似文献   

16.
Female rats fed approximately 5 mg/day/kg of body wt of nicotinic acid-14C excreted 10 per cent of the daily ingested label in bile and 57 per cent in urine. Approximately two-thirds of the label in bile was present as nicotinamide riboside. Chemical analysis of nicotinamide riboside indicates that about 7 μmoles/day/kg of body wt are excreted into bile. Chemical and radiochemical analyses both indicate that biliary nicotinamide riboside excretion may account for a major fraction of the hepatic pyridine nucleotide turnover. Nicotinamide riboside was not detected in urine, while 1-methylnicotinamide was present in urine but not in bile. Of the daily dietary intake, 6.7 per cent was excreted in bile as nicotinamide riboside while 19.6 per cent was excreted in urine as 1-methylnicotinamide. After intra peritoneal administration of 150 mg/kg of nicotinic acid or 500 mg/kg of nicotinamide, the hepatic NAD+ content increases 2 to 4-fold, accompanied by a marked increase in the turnover of this newly formed NAD+. The biliary excretion of nicotinamide riboside increases up to ten times the normal rate during this period of increased hepatic NAD+ turnover. The nicotinamide riboside excretion appears to be related to the elevation of NAD+ and is independent of whether nicotinic acid or nicotinamide is used as the precursor. Comparison of the biliary nicotinamide riboside excretion with published values for the urinary excretion of NAD+ metabolites during a similar hepatic NAD+ increase indicates that the biliary route may be a major pathway for the elimination of hepatic NAD+ metabolites. 1-Methylnicotinamide was not found in bile unless very large intravenous doses were given to animals with ligated renal pedicles. The possible role of the biliary system in pyridine nucleotide dynamics and the possible relation of biliary nicotinamide riboside excretion to the secretion of other organic cations into bile are discussed.  相似文献   

17.
We studied the biliary and renal excretion, hepatic metabolism, and hepatic subcellular distribution of [14C]metronidazole in bile fistula rats. An average of 71.1 per cent of an intraduodenal or intravenous dose of [14C]metronidazole was excreted in 24 hr, 23.9 per cent in bile and 47.6 per cent in urine. Renal pedicle ligation caused a 150 per cent increase in biliary excretion of label, whereas phenobarbital pretreatment had no effect. The majority of label in bile and urine was associated with a polar derivative, tentatively identified by thin-layer chromatography and enzymatic hydrolysis as the monoglucuronide conjugate of metronidazole. After intraduodenal administration of purified conjugated [14C]metronidazole to rats with ligated renal pedicles, only a small amount of label (12.6 per cent of dose in 24 hr) appeared in bile. Growth inhibition studies showed the glucuronide conjugate to be devoid of antimicrobial activity against a metronidazole-sensitive organism, Tritrichomonas foetus. Uptake studies indicated that these organisms were incapable of concentrating conjugated metronidazole. Fractionation of rat liver homogenates by differential centrifugation after intravenous [14C]metronidazole showed that 90 per cent of label present in liver was in the non-particulate fraction. Our results in rats indicate that metronidazole undergoes an enterohepatic circulation and that the liver plays a major role in the metabolism and excretion of this compound.  相似文献   

18.
The effect of administration of pentobarbital (P) and morphine (M) by pellet implantation on hepatic uptake and disposition of [14C]methadone was investigated using isolated perfused rat liver preparations obtained from drug- and placebo-treated animals. Placebo liver preparations excreted 36.4% of the radiolabel as metabolites of methadone in the bile after 2 hr of perfusion. P treatment resulted in a marked increase (205% of placebo) in the biliary excretion of endogenously formed metabolites of methadone. On the other hand M treatment elicited a marked decrease (57% of placebo) in the biliary excretion of endogenous metabolites of methadone. These results could not be explained by slightly altered volume of bile secretion. An examination of the pharmacokinetics of methadone revealed that rate of metabolism of methadone was increased by penfobarbital and decreased by morphine pretreatments. However, the altered rate of metabolism of meth done alone could not account for the modifications elicited by P and M on biliary excretory function. Increased biliary excretion after P was lower than would be expected due to increased metabolism of methadone. Biliary excretion of exogenously provided metabolites of methadone was slightly suppressed after M and enhanced after exposure to P. These results are suggestive of the potential for clinically significant drug interactions in drug addiction. These findings also imply that factor(s) other than bile flow and in addition to rate of metabolism play a role in the drug-induced modification of biliary excretory function.  相似文献   

19.
Distribution, excretion, and metabolism of butylbenzyl phthalate in the rat   总被引:5,自引:0,他引:5  
The disposition of butylbenzyl phthalate (BBP), a widely used plasticizer, was evaluated after oral and iv administration to rats. Male Fischer-344 rats were dosed with [14C]BBP at 2, 20, 200, or 2000 mg/kg po or 20 mg/kg iv to determine the effects of dose on rates and routes of excretion. In 24 h, 61-74% of the dose was excreted in the urine and 13-19% in the feces at 2-200 mg/kg. At the 2000-mg/kg dose, 16% of the 14C was excreted in the urine and 57% in the feces. Urinary 14C was composed of monophthalate derivatives (MP: 10-42% of the dose) and glucuronides of these monophthalate derivatives (2-21% of the dose). At 4 h after iv administration of BBP (20 mg/kg), 53-58% of the dose was excreted in the bile of anesthetized rats. No parent compound was found in the bile, but monobutyl phthalate-glucuronide and monobenzyl phthalate-glucuronide (26% and 13% of the dose, respectively) and trace amounts of free monoesters (2% of the dose) and unidentified metabolites (14% of the dose) were present. Although BBP is an asymmetric diester with the potential of forming equal amounts of monobutyl phthalate (MBuP) and monobenzyl phthalate (MBeP), larger quantities of MBuP were formed (MBuP = 44% versus MBeP = 16% of the dose). The half-lives of BBP, MP, and total 14C in blood (20 mg/kg, iv) were 10 min, 5.9 h, and 6.3 h, respectively. This study indicates that BBP is rapidly metabolized and that the major route of excretion of metabolites is biliary. These metabolites are reabsorbed and ultimately eliminated in the urine.  相似文献   

20.
[7-3H]Tetracycline and [carbonyl-14C]rafoxanide were injected intravenously into anesthetized controls and rats in which experimental fascioliasis had been induced by 20 Fasciola hepatica metacercariae. The biliary excretion (1 and 3 h, respectively) of the radioactivity consisted of approximately 4% of the administered dose. In 4-week infested rats, biliary excretion of [3H]tetracycline and hepatic levels of radioactivity were decreased, whereas bile flow did not vary and plasma clearance of the antibiotic was significantly decreased in comparison with control animals. These differences could be the result of the fascioliasis-induced decrease in the hepatic uptake of tetracycline and the limited active transport for its output into bile canaliculi. No change in [14C]rafoxanide disposition was shown in infested rats.  相似文献   

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