Demethylation metabolism

The oxidation of OPs can bring detoxication as well as activation. Oxidative attack can lead to the removal of R groups (oxidative dealkylation), leaving behind P-OH, which ionizes to PO . Such a conversion looks superficially like a hydrolysis, and was sometimes confused with it before the great diversity of P450-catalyzed biotransformations became known. Oxidative deethylation yields polar ionizable metabolites and generally causes detoxication (Eto 1974 Batten and Hutson 1995). Oxidative demethy-lation (0-demethylation) has been demonstrated during the metabolism of malathion. 

Aoyama Y, Y Yoshida, R Sato (1984) Yeast cytochrome P-450 catalyzing lanosterol 14a-demethylation. 11. Lanosterol metabolism by pnrified P-dSOj j and by intact micrososmes. J Biol Chem 259 1661-1666. 

Aoyama Y, Y Yoshida, Y Sonoda, Y Sato (1987) Metabolism of 32-hydroxy-24,25-dihydrolanosterol by pnrified cytochrome P-450j4]j]y[ from yeast. Evidence for contribntion of the cytochrome to whole process of lanosterol 14a-demethylation. J Biol Chem 262 1239-1243. 

Rosazza JP, Rammer M, Youel L (1977) Microbial models of mammalian metabolism 0-demethylations of papaverine. Xenobiotica 7(3) 133-143... 

In general, phase I reactions, such as oxidation and ra-demethylation are delayed in the neonate but are fully operational at or above adult levels by 4-6 months of age in the full-term neonate [27a-30]. Conjugation pathways, such as glucuronidation, do not approach adult values until 3 or 4 years of age. Sulfation activity does appear to reach adult levels in early infancy. For drugs that are subject to metabolism by both pathways, such as acetaminophen, the efficient activity of the sulfation pathway allows infants and children to compensate for low glucuronidation ability... 

In the case of the methylated xanthines, particularly theophylline, theobromine and caffeine, the preponderance of data on the metabolism of these compounds in man suggests that a methylated uric acid is the principal product. However, the data presented earlier proposes at best a 77 per cent accounting of the methylated xanthine administered. The question can be raised as to whether the final products observed upon electrochemical oxidation of these compounds aids these studies. Very recently studies of metabolism of caffeine have revealed that 3,6,8-trimethylallantoin is a metabolite of caffeine 48>. This methylated allantoin is, of course, a major product observed electrochemically. The mechanism developed for the electrochemical oxidation seems to nicely rationalize the observed products and electrochemical behavior. The mechanism of biological oxidation could well be very similar, although insufficient work has yet been performed to come to any definite conclusions. There is however, one major difference between the electrochemical and biological reactions which is concerned with the fact that in the former situation no demethylation occurs whereas in the latter systems considerable demethylation appears to take place. 

C]-(35)-2,3-epoxysqualene and its racemate have been prepared by two routes in a metabolically non-labile position relative to the demethylation of lanosterol to cholesterol (equation 70 and 71). The racemic [24,30-14C]-2,3-epoxysqualene, 192, has been obtained163 by condensation of (35, 3/ )-2,3-epoxytrisnorsqualene aldehyde 193 with freshly prepared 14C-labelled isopropylidenephosphorane, 194 (equation 70). 

The major metabolic pathways of the TCAs are demethylation, hydroxyla-tion, and glucuronide conjugation. Metabolism of the TCAs appears to be linear within the usual dosage range, but dose-related kinetics cannot be ruled out in the elderly. 

The major biotransformations of pseudoephedrine hydrochloride are parahydroxylation, N-demethylation, and oxidative deamination.14 The proposed pathways for the metabolism of pseudoephedrine are shown in Figure 6. 

Microbial transformations of ellipticine (15) and 9-methoxyellipticine (16) were reported by Chien and Rosazza (143, 144). Of 211 cultures screened for their abilities to transform 9-methoxyellipticine (16), several, including Botrytis alii (NRRL 2502), Cunninghamella echinulata (NRRL 1386), C. echinulata (NRRL 3655), and Penicillium brevi-compactum (ATCC 10418), achieved O-demethylation of 16 in good yield (Scheme 9). P. brevi-compactum was used to prepare 9-hydroxyellipticine (22) from the methoxylated precursor, and 150 mg of product was obtained from 400 mg of starting material (37% yield). The structure of the metabolite was confirmed by direct comparison with authentic 9-hydroxyellipticine (143). O-Demethylation is a common microbial metabolic transformation with 16 and many other alkaloids (143). Meunier et al. have also demonstrated that peroxidases catalyze the O-demethylation reaction with 9-methoxyellipticine (145). 

Sladek, N.E. and Mannering, G.J. (1969) Induction of drug metabolism. I. Differences in the mechanisms by which polycyclic hydrocarbons and phenobarbital produce their inductive effects on microsomal N-demethylating systems. Molecular Pharmacology, 5 (2), 174-185. 

Uckun, F.M., Thoen, J., Chen, H., Sudbeck, E., Mao, C., Malaviya, R., Liu, X.-P. and Chen, C.-L. (2002) CYP1A-mediated metabolism of the janus kinase-3 inhibitor 4-(4 -hydroxyphenyl)-amino-6,7-dimethoxyquinazoline structural basis for inactivation by regioselective o-demethylation. Drug Metabolism and Disposition The Biological Fate of Chemicals, 30 (1), 74—85. 

Metabolism Oxidation Glucuronidation Hydroxylation N-Demethylation Hydroxylation Plasma and hepatic esterases... 

Metabolism Glucuronidation N-demethylation Ester hydrolysis to morphine Glucuronidation demethylation (CYP2D6) Ester hydrolysis N-demethylation N-Dealkylation, then hydroxylation N-Demethylation Plasma and tissue esterases... 

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