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1.
The areca alkaloids comprise arecoline, arecaidine, guvacoline, and guvacine. Approximately 600 million users of areca nut products, for example, betel quid chewers, are exposed to these alkaloids, principally arecoline and arecaidine. Metabolism of arecoline (20 mg/kg p.o. and i.p.) and arecaidine (20 mg/kg p.o. and i.p.) was investigated in the mouse using a metabolomic approach employing ultra-performance liquid chromatography-time-of-flight mass spectrometric analysis of urines. Eleven metabolites of arecoline were identified, including arecaidine, arecoline N-oxide, arecaidine N-oxide, N-methylnipecotic acid, N-methylnipecotylglycine, arecaidinylglycine, arecaidinylglycerol, arecaidine mercapturic acid, arecoline mercapturic acid, and arecoline N-oxide mercapturic acid, together with nine unidentified metabolites. Arecaidine shared six of these metabolites with arecoline. Unchanged arecoline comprised 0.3-0.4%, arecaidine 7.1-13.1%, arecoline N-oxide 7.4-19.0%, and N-methylnipecotic acid 13.5-30.3% of the dose excreted in 0-12 h urine after arecoline administration. Unchanged arecaidine comprised 15.1-23.0%, and N-methylnipecotic acid 14.8%-37.7% of the dose excreted in 0-12 h urine after arecaidine administration. The major metabolite of both arecoline and arecaidine, N-methylnipecotic acid, is a novel metabolite arising from carbon-carbon double-bond reduction. Another unusual metabolite found was the monoacylglyceride of arecaidine. What role, if any, that is played by these uncommon metabolites in the toxicology of arecoline and arecaidine is not known. However, the enhanced understanding of the metabolic transformation of arecoline and arecaidine should contribute to further research into the clinical toxicology of the areca alkaloids.  相似文献   

2.
K11777 (N-methyl-piperazine-Phe-homoPhe-vinylsulfone-phenyl) is a potent, irreversible cysteine protease inhibitor. Its therapeutic targets are cruzain, a cysteine protease of the protozoan parasite Trypanosoma cruzi, and cathepsins B and L, which are associated with cancer progression. We evaluated the metabolism of K11777 by human liver microsomes, isolated cytochrome P450 (CYP) enzymes, and flavin-containing monooxygenase 3 (FMO3) in vitro. K11777 was metabolized by human liver microsomes to three major metabolites: N-oxide K11777 (apparent K(m) = 14.0 +/- 4.5 microM and apparent V(max) = 3460 +/- 3190 pmol. mg(-1). min(-1), n = 4), beta-hydroxy-homoPhe K11777 (K(m) = 16.8 +/- 3.5 microM and V(max) = 1260 +/- 1090 pmol. mg(-1). min(-1), n = 4), and N-desmethyl K11777 (K(m) = 18.3 +/- 7.0 microM and V(max) = 2070 +/- 1830 pmol. mg(-1). min(-1), n = 4). All three K11777 metabolites were formed by isolated CYP3A and their formation by human liver microsomes was inhibited by the CYP3A inhibitor cyclosporine (50 microM, 54-62% inhibition) and antibodies against human CYP3A4/5 (100 microg of antibodies/100 microg microsomal protein, 55-68% inhibition). CYP2D6 metabolized K11777 to its N-desmethyl metabolite with an apparent K(m) (9.2 +/- 1.4 microM) lower than for CYP3A4 (25.0 +/- 4.0 microM) and human liver microsomes. The apparent K(m) for N-oxide K11777 formation by cDNA-expressed FMO3 was 109 +/- 11 microM. Based on the intrinsic formation clearances and the results of inhibition experiments (CYP2D6, 50 microM bufuralol; FMO3 mediated, 100 mM methionine) using human liver microsomes, it was estimated that CYP3A contributes to >80% of K11777 metabolite formation. K11777 was a potent (IC(50) = 0.06 microM) and efficacious (maximum inhibition 85%) NADPH-dependent inhibitor of human CYP3A4 mediated 6'beta-hydroxy lovastatin formation, suggesting that K11777 is not only a substrate but also a mechanism-based inhibitor of CYP3A4.  相似文献   

3.
Disposition parameters of quinidine and three of its metabolism, 3-hydroxy quinidine, quinidine N-oxide, and quinidine 10,11-dihydrodiol, were determined in five normal healthy volunteers after prolonged intravenous infusion and multiple oral doses. The plasma concentrations of individual metabolites after 7 hr of constant quinidine infusion at a plasma quinidine level of 2.9 +/- (SD) 0.3 mg/L were: 3-hydroxy quinidine, 0.32 +/- 0.06 mg/L; quinidine N-oxide, 0.28 +/- 0.03 mg/L; and quinidine 10,11-dihydrodiol, 0.13 +/- 0.04 mg/L. Plasma trough levels after 12 oral doses of quinidine sulfate every 4 hr averaged: quinidine, 2.89 +/- 0.50 mg/L; 3-hydroxy quinidine, 0.83 +/- 0.36 mg/L; quinidine N-oxide, 0.40 +/- 0.13 mg/L; and quinidine 10,11-dihydrodiol, 0.38 +/- 0.08 mg/L. Relatively higher plasma concentrations of 3-hydroxy quinidine metabolite after oral dosing probably reflect first-pass formation of this quinidine metabolite. A two-compartment model for quinidine and a one-compartment model for each of the metabolites described the plasma concentration-time curves for both i.v. infusion and multiple oral doses. Mean (+/- SD) disposition parameters for quinidine from individual fits, after i.v. infusion were as follows: Vl, 0.37 +/- 0.09 L/kg; lambda 1, 0.094 +/- 0.009 min-1; lambda 2, 0.0015 +/- 0.0002 min-1; EX2, 0.013 +/- 0.002 min-1; clearance (ClQ), 3.86 +/- 0.83 ml/min/kg. Both plasma and urinary data were used to determine metabolic disposition parameters. Mean (+/- SD) values for the metabolites after i.v. quinidine infusion were as follows: 3-hydroxy quinidine: formation rate constant kmf, 0.0012 +/- 0.0005 min-1, volume of distribution, Vm, 0.99 +/- 0.47 L/kg; and elimination rate constant, kmu 0.0030 +/- 0.0002 min-1. Quinidine N-oxide: kmf, 0.00012 +/- 0.00003 min-1; Vm, 0.068 +/- 0.020 L/kg; and kmu, 0.0063 +/- 0.0008 min-1. Quinidine 10,11-dihydrodiol: kmf, 0.0003 +/- 0.0001 min-1; Vm, 0.43 +/- 0.29 L/kg; and kmu, 0.0059 +/- 0.0010 min-1. Oral absorption of quinidine was described by a zero order process with a bioavailability of 0.78. Concentration dependent renal elimination of 3-hydroxy quinidine was observed in two out of five subjects studied.  相似文献   

4.
AIMS To determine the FMO and P450 isoform selectivity for metabolism of benzydamine and caffeine, two potential in vivo probes for human FMO. METHODS Metabolic incubations were conducted at physiological pH using substrate concentrations of 0.01-10 mM with either recombinant human FMOs, P450s or human liver microsomes serving as the enzyme source. Products of caffeine and benzydamine metabolism were analysed by reversed-phase h.p.l.c. with u.v. and fluorescence detection. RESULTS CYP1A2, but none of the human FMOs, catalysed metabolism of caffeine. In contrast, benzydamine was a substrate for human FMO1, FMO3, FMO4 and FMO5. Apparent Km values for benzydamine N-oxygenation were 60 +/- 8 microM, 80 +/- 8 microM, > 3 mM and > 2 mM, for FMO1, FMO3, FMO4 and FMO5, respectively. The corresponding Vmax values were 46 +/- 2 min-1, 36 +/- 2 min-1, < 75 min-1 and < 1 min-1. Small quantities of benzydamine N-oxide were also formed by CYPs 1A1, 1A2, 2C19, 2D6 and 3A4. CONCLUSIONS: FMO1 and FMO3 catalyse benzydamine N-oxygenation with the highest efficiency. However, it is likely that the metabolic capacity of hepatic FMO3 is a much greater contributor to plasma levels of the N-oxide metabolite in vivo than is extrahepatic FMO1. Therefore, benzydamine, but not caffeine, is a potential in vivo probe for human FMO3.  相似文献   

5.
Eleven male patients from Mali with Onchocerca volvulus infections received in random order a 1200 mg single oral dose of CGP 6140 after an overnight fast and after food intake. The concentrations of CGP 6140 and of its N-oxide metabolite, CGP 13231, were measured in plasma and urine. Mean (+/- s.d.) AUC CGP 6140 values were 67.0 +/- 10.8 mumol l-1 h in fed and 22.0 +/- 17.2 mumol l-1 h in fasting patients. The mean maximum concentrations (Cmax) in plasma +/- s.d. were 12.7 +/- 2.8 mumol l-1 in fed and 4.7 +/- 4.1 mumol l-1 in fasting patients. The median time to Cmax was 3 h in fed and 2 h in fasting patients. Mean (+/- s.d.) AUC of the N-oxide metabolite was 59.9 +/- 10.7 mumol l-1 h in fed and 23.4 +/- 16.2 mumol l-1 h in fasting patients. The urinary recovery was less than 0.5% of dose for CGP 6140 in both fed and fasting conditions. It was 30.1 +/- 11.5 and 11.4 +/- 8.0% of the dose for the N-oxide metabolite in fed and fasting conditions, respectively. Variability in plasma concentrations and urinary recovery of CGP 6140 and of the N-oxide metabolite was greater in fasted patients. The low solubility of CGP 6140 in aqueous solutions at neutral pH and its higher solubility at acidic pH might explain the increase in bioavailability after food intake. The administration of CGP 6140 after food intake is therefore recommended for an optimal systemic effect.  相似文献   

6.
The involvement of flavin-containing monooxygenases (FMOs) in the formation of xanomeline N-oxide was examined in various human and rat tissues. Expressed FMOs formed xanomeline N-oxide at a significantly greater rate than did expressed cytochromes P-450. Consistent with the involvement of FMO in the formation of xanomeline N-oxide in human liver, human kidney, rat liver, and rat kidney microsomes, this biotransformation was sensitive to heat treatment, increased at pH 8.3, and inhibited by methimazole. The latter two characteristics were effected to a lesser extent in human kidney, rat liver, and rat kidney microsomes than were observed in human liver microsomes, suggesting the involvement of a different FMO family member in this reaction in these tissues. As additional proof of the involvement of FMO in the formation of xanomeline N-oxide, the formation of this metabolite by a characterized human liver microsomal bank correlated with FMO activity. The FMO forming xanomeline N-oxide by human kidney microsomes exhibited a 20-fold lower K(M) (average K(M) = 5.5 microM) than that observed by the FMO present in human liver microsomes (average K(M) of 107 microM). The involvement of an FMO in the formation of xanomeline N-oxide in rat lung could not be unequivocally demonstrated. These data and those in the literature suggest that the increased prevalence of N-oxidized metabolites of xanomeline after s.c. dosing as compared with oral dosing may be due to differences in the affinity of various FMO family members for xanomeline or to differences in exposure to xanomeline that these enzymes receive under different dosing regimens.  相似文献   

7.
Altered metabolism of valproate has been suggested as the mechanism of teratogenicity and hepatotoxicity of valproate. This study aimed at examining whether pharmacokinetics of a slow-release formulation of valproate affects valproate metabolism. Thirty-one epileptic patients were treated with fixed-doses of conventional valproate for at least 2 months. Thereafter, the drug was replaced with the same doses of slow-release formulation of valproate for 2 months. Blood samplings for determination of valproate and its metabolites by gas chromatography-mass spectrometry were performed at three time-points (just before morning dose and at 1 and 5 hr after morning dose) during both treatment phases. There was a significant difference (P < 0.005) in the mean serum concentration (+/- S.D.) of valproate after 1 hr between conventional valproate (63.1 +/- 27.9 microg/ml) and slow-release formulation of valproate (45.7 +/- 19.5 microg/ml). Mean serum concentrations (+/- S.D.) of 4-en and hydroxy metabolites after 5 hr were significantly reduced after replacement with slow-release formulation of valproate (4-en: 29.5 +/- 14.0-->23.0 +/- 15.3 ng/ml, 3-OH: 488.5 +/- 234.0-->419.6 +/- 171.1 ng/ml, 4-OH: 404.3 +/- 124.7-->342.8 +/- 147.6 ng/ml, 5-OH: 102.8 +/- 54.4-->81.0 +/- 43.6 ng/ml). The present study suggests that smaller diurnal fluctuations in valproate concentrations during treatment with slow-release formulation of valproate result in decreased formations of minor metabolites including 4-en, the most toxic metabolite.  相似文献   

8.
This report demonstrates that an Ehrlich-reagent-positive metabolite of monocrotaline and senecionine is excreted in the urine of male rats as an N-acetylcysteine conjugate of (+/-)-6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (NAC-DHP). Isolation of the metabolite employed an initial organic extraction followed by HPLC separation of remaining urinary components using a reverse-phase, polymer-based, PRP-1 column. Fast-atom-bombardment tandem mass spectrometry was used to identify the metabolite. This finding suggests that reactive metabolites of pyrrolizidine alkaloids generated in the liver can survive the aqueous environment of the circulatory system as glutathione conjugates or mercapturic acids.  相似文献   

9.
The metabolism of tamoxifen was studied in female Sprague-Dawley rat and mouse liver slices and homogenates, and the three principal tamoxifen metabolites, 4-hydroxytamoxifen, N-desmethyl-tamoxifen and tamoxifen N-oxide, were identified by HPLC using authentic standards. It was not possible to identify any of the minor metabolites such as the epoxides using this technique. The N-oxide metabolite only appeared when NADPH was added to the system; this is because the production of tamoxifen N-oxide is primarily mediated by microsomal flavin monooxygenase (FMO) which is NADPH dependent. However, this metabolite did appear in incubations with mouse liver slices only, because they are rich in flavin monooxygenases (FMOs). It did not appear in female rat or mouse liver homogenates, because the NADPH present is destroyed during homogenisation, therefore it was necessary to add NADPH to the system to produce the N-oxide metabolite. The purpose of this study was to investigate the effect of inhibitors on the biotransformation of tamoxifen by female rat and mouse liver slices and homogenates. Female rat liver slices and homogenates were incubated with the following inhibitors (1 mM): cimetidine, ascorbate, sodium azide and reduced glutathione. Cimetidine, a general P-450 inhibitor, inhibited the production of the N-desmethyl metabolite by about 80%; this is in agreement with the action of the other inhibitors. Reduced glutathione, ascorbate and sodium azide are mainly peroxidase inhibitors, so therefore from these novel and interesting results it was possible to suggest that peroxidases play a role in the metabolism of tamoxifen. This observation was also strengthened when the production of the N-desmethyl metabolite increased when horseradish peroxidase was added to the incubate. The production of 4-hydroxytamoxifen was reduced and the N-oxide metabolite was completely inhibited in the presence of peroxidase inhibitors. When rat liver homogenates was incubated with superoxide dismutase (SOD) and catalase, it was observed that the N-desmethyl metabolite disappeared completely at 60 min and the N-oxide and 4-hydroxy metabolites were completely inhibited. However, this phenomenon was only observed when SOD and catalase were preincubated for 30 min with the rat liver homogenate at 37 degrees C; without preincubation the production of these metabolites was unaffected. Finally, the effect of long incubation periods (300 min) on the production of metabolites was examined. It was found that there was a reduction in the concentration of metabolite produced after 60 min which was due to enzyme and co-factor degradation.  相似文献   

10.
Procainamide, a type I antiarrhythmic agent, is used to treat a variety of atrial and ventricular dysrhythmias. It was reported that long-term therapy with procainamide may cause lupus erythematosus in 25-30% of patients. Interestingly, procainamide does not induce lupus erythematosus in mouse models. To explore the differences in this side-effect of procainamide between humans and mouse models, metabolomic analysis using ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC-ESI-QTOFMS) was conducted on urine samples from procainamide-treated humans, CYP2D6-humanized mice, and wild-type mice. Thirteen urinary procainamide metabolites, including nine novel metabolites, derived from P450-dependent, FMO-dependent oxidations and acylation reactions, were identified and structurally elucidated. In vivo metabolism of procainamide in CYP2D6-humanized mice as well as in vitro incubations with microsomes and recombinant P450s suggested that human CYP2D6 plays a major role in procainamide metabolism. Significant differences in N-acylation and N-oxidation of the drug between humans and mice largely account for the interspecies differences in procainamide metabolism. Significant levels of the novel N-oxide metabolites produced by FMO1 and FMO3 in humans might be associated with the development of procainamide-induced systemic lupus erythematosus. Observations based on this metabolomic study offer clues to understanding procainamide-induced lupus in humans and the effect of P450s and FMOs on procainamide N-oxidation.  相似文献   

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