Urinary sulfate metabolite

The lactam derivative dibenz[h/]l 4-oxazepin-ll-(lOH)-one is a primary metabolic product of metabolism and a direct precursor of the urinary hydroxylated metabolites. In rats, the lactam, a dihydro-CR metabolite, an amino alcohol of CR, and an arene oxide are metabolites in CR degradation. In the rat, the major mechanism for elimination is sulfate conjugation and biliary excretion to a limited extent. Phase I metabolism by microsomal mixed fimction oxidases involves reduction of CR to the amino alcohol, oxidation to form the lactam ring, and hydroxylation to form the hydroxylactams. Phase II conjugation reactions sulfate the hydroxylactam intermediates for renal elimination. Amino alcohol intermediates are conjugated with glucuro-nide for biliary secretion. 

The thermospray LC/MS analysis of a major urinary sulfate ester metabolite of SK F 86466 is shown in Figure 7. A weak ammonium adduct was observed at m/z 295, 297 with an isotope distribution consistent with the proposed structure. The major fragment ion at m/z 182, 184 occurs from loss of the sulfate ester moiety. The position of sulfation at either C7 or C9 of the molecule was determined by proton NMR NOE difference studies (data not shown). No protonated molecular ion was observed for this sulfate ester this would be expected, based on the proton affinity of the highly acidic sulfate ester moiety. 

Cawley AT, Kazlauskas R. et al. Determination of urinary steroid sulfate metabolites using ion paired extraction. J Chromatogr B Analyt Technol Biomed Life Sci2005 825(l) l-10. 

A metabolic study in 10 healthy subjects found that the clearance of paracetamol 1.5 g was almost halved (from 6.23 to 3.42 mL/minute per kg) when it was taken 1 hour after a 1-g dose of probenecid. The amount of unchanged paracetamol in the urine stayed the same, but the glucuronide metabolite fell sharply. Another study in 11 subjects also found that probenecid 500 mg every 6 hours almost halved (from 329 to 178 mL/minute) the clearance of a 650-mg intravenous dose of paracetamol. The urinary excretion of the glucuronide metabolite was decreased by 68% and the excretion of the sulfate metabolite increased by 49%. These studies suggest that probenecid inhibits paracetamol glucuronida-tion, possibly by inhibiting glucuronyltransferase. See also paracetamol , (p.l33). The praetical consequences of this interaction are uncertain but there seem to be no adverse reports. 

The metabolism of an oral dose of 50-100 mg/kg "C-1,3-DNB was followed in rabbits (Parke 1961). Of the metabolites detected in urine, 30% were conjugated with glucuronic acid and 6% with sulfate. The major urinary metabolites of 1,3-DNB were 2,4-diaminophenol (31%), 1,3-phenylenediamine (25%), 1,3-nitroaniline (18%), and 2-amino-4-nitrophenol (14%). Other minor metabolites comprising about 20% of the label were oxidation and reduction products and azoxy dimers. 

LC/ESI-MS analyses were applied to determine urinary glucuronidated and sulfated tea catechins after the administration of green tea to humans, mouse and rats [109]. The major conjugates were identified as monoglucuronides and monosulfates of EGC and EC. Besides these metabolites, also G-methyl-EGC-G-glucuronides, O-sulfates and O-methyl-EC-O-sulfates in human urine were detected. Furthermore, the ring-fission metabolites of EGC and (-)-epicatechin, 5-(3 ,4 ,5 -trihydroxyphenyl)-y-valerolactone and 5-(3 ,4 -dihydroxyphenyl)- valerolactone respectively, have been detected in the monoglucuronide and monosulfate forms. 

Similarly in 2005, Wang et al. identified the microbial metabolites of resvera-trol in rats (Table 13.3). Urine samples were obtained after oral administration of 20 mg/kg to Sprague-Dawley rats. They identified resveratrol-glucuronide, resveratrol-sulfate, 7,8-dihydroresveratrol, and 7,8-dihydroresveratrol-sulfate as the main 12-h urinary metabolite in rats by mass spectrometry after are SPE treatment [Wang et al., 2005]. 

Urinary excretion mainly took place in the first 4 h after consumption (77% of total excretion), although resveratrol metabolites remained in urine between 12and24 h after intake. Free resveratrol, 2 glucuronides, and the 3-sulfate excreted in the urine 24 h after intake were below 0.04, 2, 9, and 11 % of the 0.5 mg provided, respectively. At higher dose (5 mg) resveratrol, glucuronides and sulfate recoveries in the urine at 24 h were 0.1, 0.5, 3, and 5% of the dose, respectively. In urinary excretion, the sulfate forms were also higher than the glucuronide and free forms. 

Studies on the metabolic fate of phenol in several species have indicated that four urinary products are excreted (Figure 9.5). Although extensive phenol metabolism takes place in most species, the relative proportions of each metabolite produced varies from species to species. In contrast to the cat, which selectively forms sulfate conjugates, the pig excretes phenol exclusively as the glucuronide. This defect in sulfate conjugation in the pig is restricted to only a few substrates, however, and may be due to the lack of a specific phenyl sulfotransferase because the formation of substantial amounts of the sulfate conjugate of 1-naphthol clearly indicates the occurrence of other forms of sulfotransferases. 

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