Methylation metabolites

Inorganic arsenic plus methylated metabolites in End of workweek 35 pg/g As/I B... 

A major metabolite was detected in the ethanol extract of 2,7-dichlo-rodioxin-treated soils. The metabolite was less mobile than DCDD in benzene-acetonitrile on TLC. The metabolite was eluted from the silica gel and methylated with diazomethane. The methylated metabolite was rechromatographed in benzene and migrated to the solvent front, suggesting a polar group on the non-methylated metabolite. 

Separation of amino acids Histamine and its methylated metabolite in human urine samples... 

Changes in catecholamines and 3-O-methyl metabolite concentrations in human plasma Erythropoietin in pharmaceutical products 3,4-methylenedioxymethamphetamine, 3,4-methylenedioxyamphetamine, amphetamine, and methamphetamine in rat urine Azoxystrobin, kresoxim-methyl, and trifloxystrobin fungiddes ... 

A potentially relevant association of 6-MP dosing and its metabolite distribution was suggested recently by data from the Pediatric Oncology Group 9605 trial (129). In this trial, daily 6-MP was compared with twice-daily administration during maintenance therapy of standard-risk childhood ALL. RBC 6-TGN and methylated metabolite levels were measured in a randomly selected subset of patients. 

Schmiegelow and colleagues speculated that dose escalation of 6-MP may lead to increased intracellular levels of methylated metabolites, such as 6-MMPR, which inhibit purine de novo synthesis in leukemic lymphoblasts of patients with high TPMT activity and therefore, lead to a delay of these cells in S phase under maintenance treatment and potential regrowth after treatment discontinuation. 

Mirtazapine, amoxapine, and maprotiline have tetracyclic structures. Amoxapine is the /V-methylated metabolite of loxapine, an older antipsychotic drug. Amoxapine and maprotiline share structural similarities and side effects comparable to the TCAs. As a result, these tetracyclics are not commonly prescribed in current practice. Their primary use is in MDD that is unresponsive to other agents. 

Perez-Vizcaino F, Ibarra M, Cogolludo AL, Duarte J, Zaragoza-Arnaez F, Moreno L, Tamargo J. 2002. Endothelium-independent vasodilator effects of the flavonoid quercetin and its methylated metabolites in rat conductance and resistance arteries. J Pharmacol Exp Ther 302 66-72. 

Kenyon, E.M., Del Razo, L.M. and Hughes, M.F. (2005a) Tissue distribution and urinary excretion of inorganic arsenic and its methylated metabolites in mice following acute oral administration of arsenate. Toxicological Sciences, 85(1), 468-75. 

Offergelt, J.A., Roels, H., Buchet, J.P. et al. (1992) Relation between airborne arsenic trioxide and urinary excretion of inorganic arsenic and its methylated metabolites. British Journal of Industrial Medicine, 49(6), 387-93. 

With the strong sensitivity of multiple MRMs as a method of metabolite detection, one can assume that this method is superior to all others. However, like any analytical technique, a number of limitations exist for this type of experiment. First, any metabolites that are not predicted will not be detected. Single MS, precursor, and neutral loss scans are not subject to this limitation. Second, the more modifications that take place on the parent, the more number permutations of MRMs are required. For example, to detect an oxidation and methylation metabolite, as shown in the following table, four theoretical MRMs would be required ... 

An example of genetic susceptibility to toxic effects of a drug is provided by mercaptopurine drugs, such as 6-mercaptopurine, used as antitumor agents. The active forms of these drugs are the methylated metabolites, as shown for the methylation of 6-mercaptopurine in Reaction 8.6.1 ... 

R. B. Smith, J. C. Glade, and D. W. Humphrey, High-performance liquid chromatographic separation of apomorphine and its o-methyl metabolites, J. Chromatogr., 772 570 (1979). 

K. Harrington-Brock, T.W. Smith, C.L. Doerr, and M.M. Moore, Mutagenicity of the human carcinogen arsenic and its methylated metabolites, monomethylarsenic... 

The formation of 0-methylated metabolites of THP, and of berbine 124, with rat liver microsomal enzymes was investigated in some detail 212,213). It was shown by Davis and colleagues that intraventricular application of racemic and optically active THP and of berbine 124 led after 1 hr to the formation of metabolites which were identified and quantitated by GC-MS methods. The results are summarized in Fig. 30. It can be seen that O-methylation of the hydroxy group at C-6 in both enantiomers of THP and the racemate necessary to connect with norreticuline (121) only was a minor pathway, and that O-methylation of the hydroxy group at C-7 was the preferred route. 0-MethyIation of the hydroxy group at C-11 in berbine 124 was preferred over that at C-10, as was the O-methylation of the hydroxy group at C-2 over that at C-3. 

Disposition in the Body. Readily absorbed after oral administration about 75% of the dose is absorbed. Up to 40% of an oral dose is excreted in the urine as unchanged drug, about 3% as captopril disulphide and about 30% as polar metabolites. Excretion in the urine is rapid, about half the dose being excreted within the first 4 hours. An 5-methyl metabolite has been identified in plasma and urine. 

O-methyl metabolite, with up to about 15% of the dose as unchanged drug after inhalation or oral administration, 68 to 94% of a dose is excreted as conjugated isoprenaline, with about 2 to 8% of a dose as the 3-0-methyl conjugate and less than 5% as unchanged drug or free 3-0-methylisoprenaline small amounts of a dose are excreted in the bile, mainly as metabolites. 

Moore, M.M., Harrington Brock, K., Doerr, C.L. (1997). Relative genotoxic potency of arsenic and its methylated metabolites. Mutat. Res.-Rev. Mutat. Res. 386 279-90. 

OSHA PEL TWA 500 g(As)/m3 ACGIH TLV BEL 35 n (As)/L inorganic arsenic and methylated metabolites in urine SAFETY PROFILE Poison by ingestion and intravenous routes. Human systemic effects by ingestion respiratory system, endocrine system, dermatitis, and fever. Human systemic effects by intravaginal route hallucinations, distorted perceptions, convulsions, nausea or vomiting, decreased urine volume, and fever. Mutation data reported. See also ARSENIC COMPOUNDS. When heated to... 

ACGIH TLV TLV 0.01 mg/m Confirmed Human Carcinogen BEL 35 (As)/L inorganic arsenic and methylated metabolites in urine... 

ACGIH TLV TWA 0.01 mg/m Confirmed Human Carcinogen BEI 35 (As)/L inorganic arsenic and methylated metabolites in urine DFG MAK Human Carcinogen NIOSH REL CL 2 g(As)/mVl5M DOT CLASSIFICATION 6.1 Label Poison SAFETY PROFILE Confirmed human carcinogen. Poison by ingestion. Moderately toxic by skin contact. When heated to decomposition it emits toxic fumes of arsenic. 

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