Unidentified metabolite

Recently, Bryant t al. (70) examined the metabolism of 1,8-dinitropyrene in several S. typhimurium strains and found reduction to l-amino-8-nitropyrene and 1,8-diaminopyrene. In addition, other unidentified metabolites were detected in strains which were sensitive to 1,8-dinitropyrene-induced mutations (TA98 and TA98NR) but not in the resistant strains, TA98/1,8-DNP and TA98NR/1,8-DNP6. 

When 20 mg/kg of methimazole was administered i.p. or orally to rats, urinary methimazole glucuronides accounted for 36-48% of the dose in 24 hours. The only other urinary metabolite accounted for 10-20% and was not characterized. An additional 14-20% of methimazole was excreted unchanged in 24 hour urine. The bile contained methimazole glucuronide and two unidentified metabolites. One of which was the same as the unidentified urinary metabolites. Plasma proteins bound 5% of methimazole which had no affinity for any specific tissue. Methimazole had a much greater CHCI3/H2O partition coefficient and 1 0 solubility than did propylthiouracil. Between 77 and 95% of the methimazole was excreted in the urine and approximately 10% in the bile. Since fecal excretion was neglegible an enter-ohepatic circulation was present. The half life of urinary excretion was 5-7 hours regardless of the route of administration (15). 

The metabolism of C-DEHP by rainbow trout liver subcell-ular fractions and serum was studied by Melancon and Lech (14). The data in Table VI show that without added NADPH, the major metabolite produced was mono-2-ethylhexyl phthalate. When NADPH was added to liver homogenates or the mitochondrial or microsomal fractions, two unidentified metabolites more polar than the monoester were produced. Additional studies showed that the metabolism of DEHP by the mitochondrial and the microsomal fractions were very similar (Figure 1). Both fractions show an increased production of metabolites of DEHP resulting from addition of NADPH and the shift from production of monoester to that of more polar metabolites. The reduced accumulation of monoester which accompanied this NADPH mediated production of more polar metabolites may help in interpreting the pathway of DEHP metabolism in trout liver. This decreased accumulation of monoester could be explained either by metabolism of the monoester to more polar metabolites or the shift of DEHP from the hydrolytic route to a different, oxidative pathway. The latter explanation is unlikely because in these experiments less than 20% of the DEHP was metabolized. 

Similarly, in vivo metabolism of p-nitroanisole has been demonstrated by formation of a more polar, unidentified metabolite revealed following extraction and TLC (Benzene MeOH, 95 5, Silica gel G, 0.25 mm). Indication of in vitro anisole metabolism has also been obtained, but the nature of metabolites is uncertain. For the present, these observations are con-... 

Harmine and harmol are metabolized by three liver microsomes to 6-hydroxy-7-methoxyharman and 3- or 4-hydroxy-7-methoxyharman, which are further metabolized to unidentified metabolites (Tweedy and Burke 1987). Protein binding of harmine and harmol occurs, and is dependent on metabolism alkalinity. 

Reversible reduction to sulphide and oxidation to sulphone + unidentified metabolite... 

Matsumura and Bousch (1966) isolated carboxy lest erase (s) enzymes from the soil fungus Trichoderma viride und a bacterium Pseudomonas sp., obtained from Ohio soil samples, that were capable of degrading malathion. Compounds identified included diethyl maleate, desmethyl malathion, carboxylesterase products, other hydrolysis products, and unidentified metabolites. The authors found that these microbial populations did not have the capability to oxidize malathion due to the absence of malaoxon. However, the major degradative pathway appeared to be desmethylation and the formation of carboxylic acid derivatives. 

Nitrophenol, paraoxon, and three unidentified metabolites were identified in a model ecosystem containing algae, Daphnia magna, fish, mosquitoes, and snails (Yu and Sanborn, 1975). 

Bezalel et al. (1996) reported that the white rot fungus Pleurotus ostreatus, grown in basidiomycetes rich medium, metabolized 94% of the phenanthrene added. Approximately 52% was converted to /rans-9,10-dihydroxy-9,10-dihydrophenanthrene (28%), 2,2 -diphenic acid (17%), and unidentified metabolites (17%). In addition, 3% was mineralized to carlaon dioxide. Sack et al. (1997) reported that phenanthrene was degraded by an Aspergillus niger sixain isolated from a mineral oil-contaminated soil in La Plata, Argentina. The major metabolite was identified via GC/MS as 1-methoxyphenanthrene. Two minor metabolites identified were 1- and 2-phenanthrol. 

CASRN 60-51-5 molecular formula C5H12NO3PS2 FW 229.30 Soil Duff and Menzer (1973) reported that in moist soils, dimethoate is converted to the oxygen analog, dimethoxon (0,0-dimethyl-5-(W-methylcarbamoylmethyl) phosphorothiolate) and two unidentified metabolites. The degradation rate of dimethoate in three different soils increased almost two-fold with a 10 °C increase in temperature (Kolbe et al., 1991). The reported half-lives of dimethoate in a humus-rich sandy soil, clay loam, and heavy clay soil at 10 and 20 °C were 15.3, 10.3, 15.5 d and 9.7, 4.8, 8.5 d, respectively. 

Soil/Plant In soils and plants, monuron is demethylated at the terminal nitrogen atom coupled with ring hydroxylation forming 3-(2-hydroxy-4-chlorophenyl)urea and 3-(3-hydroxy-4-chloro-phenyl)urea (Hartley and Kidd, 1987). Wallnbefer et al. (1973) reported that the soil microorganism Rhizopus Japonicus degraded monuron into 3-(4-chlorophenyl)-l-methylurea. However, in the presence of Pseudomonas or Arthrobacter sp., monuron degraded to 2,4-di-chloroaniline, sj/ 3-bis(3,4-dichlorophenyl)urea, and unidentified metabolites (Janko et al., 1970). The reported half-life in soil is 166 d (Jury et al., 1987). 

Felbamate- Partial (adults) Partial/generalized assoc, with Lennox-Gastaut syndrome (children) 22 to 25 40% to 50% unchanged in urine 40% as unidentifie metabolites and conjugates... 

A full characterization of the metabolic pathways of CPT-11 in human cancer patients has not been undertaken. The incomplete recovery of the irinotecan dose based on urine and bile determinations of irinotecan, SN-38, and SN-38 glucuronide suggests the presence of additional unidentified metabolites. Recently, a major metabolite, 7-ethyl-10-[4-A-(5-aminopenatoic acid)-l-piperidino]carbonyloxycamptothecin, has been identified in dogs and humans, suggesting the presence of an additional metabolic pathway (18). Renal clearance has not been reported to be a major route of elimination for these compounds in humans. 

Leaves contained 55% of the label as the parent compound dichlofluanid, 35% as very polar unidentified metabolites and 10% as thiazolidine-2-thione-4-carboxylic acid. A small amount (0.2%) was bis-(fluo-rodichloromethyl) disulfide as confirmed by two dimai-sional tic and MS. This amount is probably less than was actually present as the work up procedures were not optimized to detect such a relatively volatile... 

Early studies (in the 1970s) on the pharmacokinetics of (+)-catechin revealed that this flavanol is absorbed from the gastrointestinal tract following administration to healthy volunteers (4.2 g in the form of gelatin capsules) [100]. (+)-Catechin was excreted in the urine together with several unidentified metabolites, and the amount excreted within 24 h was about 7.5% of the administered dose. 

Following oral administration of radiolabeled furosemide, excretion was reported to be almost complete within 3 days in rats (96-98%) and dogs (98-99%). Rat urine contained 40-50% of the parent drug, 30% 4-chloro-5-sulfamoyl-anthranilic acid, and four unidentified metabolites that accounted for the rest of the administered radioactivity. In contrast, urine of dog and monkey contained 85% unmetabolized furosemide, 7% 4-chloro-5-sulfamoyl-anthranilic acid, and the remainder was due to unidentified metabolites. Following intramuscular injection of 5 mg furosemide/kg bw in cattle, the half-life for plasma elimination was estimated at 4.3 h. In contrast, the half-life of furosemide in cattle was reported to be less than 1 h following intravenous administration. 

In addition to the previously reported bis(2,3-dibromopropyl) phosphate and 2,3-dibromopropanol, Nomcir and Matthews (1983) characterized four additional metabolites by mass spectrometry, that arose from further hydrolysis and dehydrobromination of the 2,3-dibromopropanc moiety, namely 2-bromo-2-propenyl-2,3-dibromopropyl phosphate, bis(2-bromo-2-propenyl) phosphate, 2,3-dibromopropyl phosphate and 2-bromo-2-propenyl phosphate. All six metabolites were found in 24-h urine and 3-h bile, with bis(2-bromo-2-propcnyl) phosphate and 2-bromo-2-propenyl phosphate predominating in urine, while bis(2,3-dibromopropyl) phosphate and 2-bromo-2-propenyl-2,3-dibromopropyl phosphate were the major metabolites identified in bile 67% of urinary and 47% of biliary were accoimted for by a variety of unidentified metabolites. 

Male Fischer 344 rats were exposed by inhalation to 1% 2-chloro-1,1,1 -trifluoroethane for 2 h and then urine was collected for 24 h. Urinary metabolites identified by 19F nuclear magnetic resonance and gas chromatography/mass spectrometry were 2,2,2-trifluoroethyl glucuronide (16%), trifluoroacetic acid (14%), trifluoroacetaldehyde hydrate (26%), trifluoroacetaldehyde-urea adduct (40%) and inorganic fluoride (3%). A minor, unidentified metabolite was also detected. No covalent binding of fluorine-containing metabolites was observed in the liver and kidney from the exposed rats (Yin et al., 1995). In-vitro incubation of 2-chloro-1,1,1-trifluoroethane with rat liver microsomes and an NADPH-generating system has been shown to involve a dechlorination reaction (Salmon et al., 1981) that produced trifluoroacetaldehyde hydrate as the only metabolite (Yin et al., 1995). 

FIGURE 21-44 Regulation of cholesterol formation balances synthesis with dietary uptake. Glucagon promotes phosphorylation (inactivation) of HMG-CoA reductase insulin promotes dephosphorylation (activation). X represents unidentified metabolites of cholesterol that stimulate proteolysis of HMG-CoA reductase. 

In addition to the epimerization at C-3 discussed above 187), iV-acetyl-tomatidine (185) is converted to the corresponding 3-ketone 193 and the A1,4-dien-3-one 194 by N. restrictus when the incubation times are prolonged 189). TV-Methyltomatidine 187 is similarly transformed to 195 together with other unidentified metabolites 189). The structures of 193-195 were again confirmed by MS, IR, and UV analysis. 

In Figure 5, typical chromatograms of plasma components of DIL are shown for transdermal and oral deliver. The peaks 1, 2, and 3 are, respectively, verapamil as the internal standard, DIL and deAcDIL. The peaks 4 and 5 are unidentified metabolites (12, 13). Both the extent and number of different metabolites are less in topical delivery. Skin metabolism and absorption of ionized species is virtually unknown and remains an intriguing area for study. 

Disposition in the Body. Readily and almost completely absorbed after oral administration. Up to about 30% of a dose is excreted unchanged in the urine in 48 hours the remainder is excreted as unidentified metabolites. 

Disposition in the Body. Readily absorbed after inhalation and also absorbed after ingestion or through the skin the rate of absorption is increased by the concomitant ingestion of alcohol. It is excreted mainly from the lungs as carbon tetrachloride and carbon dioxide excretion in the urine as urea and an unidentified metabolite, and elimination in the faeces also occur. 

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