Drug metabolism hydroxylation

The O-dealkylation of ethers, while not as frequently encountered as N-dealkylation in drug metabolism studies, is still a common metabolic pathway. Mechanistically it is less controversial than N-dealkylation in that it is generally believed to proceed by the HAT pathway, i.e., a-hydrogen atom abstraction followed by hydroxyl radical rebound, and not a SET pathway (Fig. 4.58). The product of the reaction is unstable, being a hemiacetal or hemiketal depending on the number of hydrogens on the a-carbon, which dissociates to generate an alcohol and an aldehyde or ketone. 

Iida, I., Miyata, A., Arai, M., Hirota, M., Akimoto, M., Higuchi, S., Kobayashi, K. and Chiba, K. (2004) Catalytic roles of CYP2C9 and its variants (CYP2C9 2 and CYP2C9 3) in lomoxicam 5 -hydroxylation. Drug Metabolism... 

Wedlund, P.J., Aslanian, W.S., McAllister, C.B., Wilkinson, G.R. and Branch, R.A. (1984) Mephenytoin hydroxylation deficiency in Caucasians frequency of a new oxidative drug metabolism polymorphism. Clinical Pharmacology and Therapeutics, 36 (6), 773-780. 

Palamanda, J., Feng, W.W., Lin, C.C. and Nomeir, A.A. (2000) Stimulation of tolbutamide hydroxylation by acetone and acetonitrile in human liver microsomes and in a cytochrome P-450 2C9-reconstituted system. Drug Metabolism and Disposition, 28 (1), 38-43. 

Alexandre, V., Ladril, S., Maurs, M. and Azerad, R., Microbial models of animal drug metabolism Part 5. Microbial preparation of human hydroxylated metabolites of irbesartan. J. Mol. Catal. B Enzymatic, 2004, 29, 173-179. 

In chickens a pattern similar to a capacity limited-elimination was noticed. The cause may be either a capacity limitation in the SDM metabolism (hydroxylation ) of SDM or extensive drug reabsorption from the cloaca occurring at night(known as chrono-pharma-cokinetics). In the chicken, 58 % of the intravenously administered dose is lost, which is also reported for other birds (24). Thus birds must possess additional metabolic pathways. 

Cytochromes P450 form a very large group of heme enzymes that catalyze the hydroxylation of a variety of substrates. They are important in drug metabolism, in cholesterol and steroid hormone biosynthesis, and in numerous other pathways. They have been found to participate in reactions other than hydroxyla-tions. 

Adverse environmental conditions or stimuli, which create stress in an animal, may influence drug metabolism and disposition. Cold stress, for instance, increases aromatic hydroxylation, as does stress due to excessive noise. It should be noted that the microsomal monooxygenases show a diurnal rhythm in both rats and mice, with the greatest activity at the beginning of the dark phase. 

Kalow W, Otton SV, Kadar D, Endrenyi L, Inaba T. Ethnic difference in drug metabolism debrisoquine 4-hydroxylation in Caucasians and Orientals. Can J Physiol Pharmacol 1980 58 1142-1144. 

Wedlund PJ, Aslanian WS, McAllister CB. Mephenytoin hydroxylation deficiency in Caucasians frequency of a new oxidative drug metabolism polymorphism. Clin Pharmacol Ther 1984 36 773-780. 

Wilkinson GR, Guengerich FP, Branch RA. Genetic polymorphism od S-mephenytoin hydroxylation. In Kalow W, ed. Pharmacogenetics of Drug Metabolism. New York Pergamon Press Inc., 1992 657-685. 

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