Drug metabolism methylation

Ferrero, J.L., Thomas, S.B., Marsh, K.C., Rodrigues, A.D., Uchic, J.T. and Buko, A.M. (2002) Implication of P450-metabolite complex formation in the nonlinear pharmacokinetics and metabolic fate of ( )-(l R, 3R )-3-phenyl-l-[(l, 2, 3, 4 -tetrahydro-5, 6 -methylene-dioxy-l -naphthalenyl) methyl] pyrrolidine methanesulfonate (ABT-200) in dogs. Drug Metabolism and Disposition, 30 (10), 1094-1101. 

As with adults, the primary organ responsible for drug metabolism in children is the liver. Although the cytochrome P450 system is fully developed at birth, it functions more slowly than in adults. Phase I oxidation reactions and demethylation enzyme systems are significantly reduced at birth. However, the reductive enzyme systems approach adult levels and the methylation pathways are enhanced at birth. This often contributes to the production of different metabolites in newborns from those in adults. For example, newborns metabolize approximately 30% of theophylline to caffeine rather than to uric acid derivatives, as occurs in adults. While most phase I enzymes have reached adult levels by 6 months of age, alcohol dehydrogenase activity appears around 2 months of age and approaches adult levels only by age 5 years. 

Since liver is the most important organ for metabolism investigations the procedures described here focus on liver cytosol exemplarily. Liver cytosol fraction contains soluble Phase I and Phase II enzymes which play an important role in drug metabolism (Brandon 2003). These are alcohol and aldehyde dehydrogenases, epoxide hydrolases, sulfotransferases, glutathione S transferase, N-acetyl transferases, and methyl transferases. Therefore, in cytosolic preparations these biotransformation steps can be studied. Cytosolic fractions are commercially available (BDGentest, Invitro Technologies, Xenotech and others) or easy to prepare, alternatively. 

Hewitt, G.G., J. Perkins and S.A.M. Hotchkiss (2000). Metabolism of fluroxypyr, fluroxypyr methyl ester, and the herbicide fluroxypyr methylheptyl ester. I. During percutaneous absorption through fresh rat and human skin in vitro. Drug Metabol Disp., 28, 748-754. 

Chui et al, [96] have reported that PCDE 74 (2,4,4, 5-tetraCDE) induce 7-ethoxycoumarin O-deethylase activities in trout and PCDE 28 (2,4,4-triCDE) and PCDE 74 (2,4,4, 5-tetraCDE) in rats. The effects of PCDEs were studied by administering PCDEs 100 mg kg 1 day 1 to rats and trout for three days. Chui et al. [96] classified PCDE 28 as a phenobarbital (PB)-type inducer and PCDE 74 a mixed-type inducer. Due to the fact that PCDEs cannot adopt planar configuration, it was suggested that PCDEs cannot act as 3-methyl chloranthrene(MC)-type inducers unlike non-orfho-PCBs. PCBs that are not acutely toxic can still induce toxic and biochemical responses and are PB-type inducers of hepatic drug-metabolizing enzymes [79]. 

Stevens JL, Bakke JE (1990) S-methylation. In Mulder GJ (ed) Conjugation reactions in drug metabolism an integrated approach. Taylor and Francis, London, p 251... 

A number of examples of genetic polymorphisms in drug metabolism have now been identified, involving oxidation, S-methylation, and acetylation., as shown in Table 4. These polymorphisms were initially identified by adverse drug reactions occurring in distinct... 

Akesson B and Jonsson BAG (1997) Major metabolic pathway for N-methyl-2-pyrrolidone in humans. Drug Metabolism and Disposition 25 267-269. 

Drug metabolism includes phase I reactions (i.e., oxidation, reduction, hydrolysis) andphase II conjugation reactions (i.e., acetylation, glucuronidation, sulphation, methylation) (see Table 4). 

A recent study has employed deuterium labeling to show that the mechanism for the oxidative N-demethylation of nicotine may involve two modes of breakdown for a proposed carbinolamine intermediate, dealkylation with formaldehyde formation and dehydration to an iminium ion.72 The formation of such an sp2-hybrid intermediate may help to explain why both a primary and substantial / -secondary deuterium isotope effect were observed for the N-deethylation of the antiarrhythmic agent, lidocaine.73 In contrast, only a primary isotope effect was observed on the rate of oxidative O-deethylation of deuterated analogs of the analgesic, phenacetin. 77 These results indicate differences in the mechanism of oxidative 0- and N-dealkylation. A final example of the use of secondary deuterium isotope effects in studying enzymes involved in drug metabolism revealed an SN-2-like transition state for the transfer of a methyl group catalyzed by catechol-O-methyl transferase.73... 

DR Thakker, CR Creveling. O-Methylation. In GJ Mulder, ed. Conjugation Reactions in Drug Metabolism An Integrated Approach. London Taylor Francis, 1990, pp 193-232. 

Methylation Reactions. Figure 13.15 summarizes the main methylation reactions seen in drug metabolism. 0-Methylation is a common reaction of compounds containing a catechol moiety (reaction 1), with a usual re-gioselectivity for the meta position. The sub-... 

MT family of enzymes catalyzes the O-, S-, or N-methylation of drugs, hormones, and neurotransmitters, and utilizes S-adenosyl-L-methionine (SAM) as a methyl donor. Catechol-O-methyltransferase (COMT) is the most extensively investigated drug-metabolizing MT. It plays an important role in the biotransformation of both endogenous and exogenous catechols. COMT has a rather broad substrate specificity for structures that contain catechol moieties and is often involved in the methylation of... 

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