Drug disposition oxidative metabolism

Zhang, D., Zhang, H., Aranibar, N. et al. (2006) Structural elucidation of human oxidative metabolites of muraglitazar use of microbial bioreactors in the biosynthesis of metabolite standards. Drug Metabolism and Disposition The Biological Fate of Chemicals, 34, 267-280. 

Wynalda, M.A., Hauer, M.J. and Wienkers, L.C. (1998) Human biotransformation of bropirimine. Characterization of the major bropirimine oxidative metabolites formed in vitro. Drug Metabolism and Disposition, 26 (10), 1048-1051. 

Wing LM, Miners JO. Cotrimoxazole as an inhibitor of oxidative drug metabolism effects of trimethoprim and sulphamethoxazole separately and combined on tolbutamide disposition. Br J Clin Pharmacol 1985 20(5) 482-5. 

Vuppugalla R, Mehvar R (2004) Hepatic Disposition and Effects of Nitric Oxide Donors Rapid and Concentration-Dependent Reduction in the Cytochrome P450-Mediated Drug Metabolism in Isolated Perfused Rat Livers. J Pharmacol Exp Ther (in press)... 

Disposition in the Body. Rapidly and completely absorbed after oral administration, with maximum plasma concentrations achieved after one to two hours. It is distributed throughout the body. The main metabolic reaction is oxidation to paracetamol through which the analgesic and antipyretic effects of the drug are chiefly exerted paracetamol is then conjugated with glucuronic acid or sulphate. A minor reaction is deacetylation of... 

Disposition in the Body. Rapidly absorbed after oral administration bioavailability almost 100%. Metabolic reactions include V-demethylation and oxidation to uric acid derivatives. About 85% of a dose is excreted in the urine in 48 hours with up to 40% of the dose as 1-methyluric acid, 10 to 15% as 1-methylxanthine and up to 35% as 5-acetylamino-6-formylamino-3-methyluracil and 5-acetylamino-6-amino-3-methyluracil other metabolites excreted in the urine include theophylline, 1,7-dimethylxanthine (paraxanthine), 7-methylxanthine, and 1,3-dimethyluric acid. Less than 10% is excreted in the urine as unchanged drug. The extent of V-acetylation is genetically determined. Caffeine, theophylline, theobromine, and paraxanthine are found in plasma from dietary sources especially coffee, tea and cocoa. An average cup of coffee or tea contains approximately 100 mg of caffeine. 

Disposition in the Body. Absorbed after oral administration. Metabolic reactions may include A -oxidation, hydroxylation, and amide hydrolysis it is possible that 2-hydroxydextromora-mide is a major metabolite. Excreted in the urine, partly as unchanged drug. 

Disposition in the Body. Readily absorbed after oral administration, but undergoes extensive first-pass metabolism by N-dealkylation and oxidative deamination to form monodesmethyl and didesmethyl metabolites, and diphenylmethoxyacetic acid which may be conjugated with glutamine or glycine bioavailability about 50%, Up to 65% of a dose is excreted in the urine in 96 hours. The major urinary metabolite appears to be diphenylmethoxyacetic acid in free or conjugated form very little is excreted as unchanged drug. 

Disposition in the Body. Slowly but completely absorbed following oral administration. It appears to undergo significant first-pass metabolism bioavailability about 70%. After intravenous administration, about 57% of a dose is excreted in the urine and 30% in the faeces over a period of 21 days less than 10% of the dose is excreted as unchanged drug. The principal metabolite is the desmethyl derivative, which has been shown to be active in animals, but hydroxylation also occurs to form phenolic derivatives which may be further converted to aromatic methoxy ethers or excreted as glucuronide conjugates A -oxidation also occurs and maprotiline A -oxide has been reported to be active numerous minor metabolites have been identified in urine. 

Disposition in the Body. About 10% of a dose is concentrated in the brain within 1 minute of an intravenous injection and it is then rapidly distributed throughout the body, eventually accumulating in body fat about 50% of a dose accumulates in this way after 30 to 90 minutes. The very short action of thiopentone is due to the brief a-phase half-life and the redistribution of the drug from the brain to other fatty tissues. Metabolic reactions include co-hydroxylation, further oxidation and, to a lesser extent, desulphuration to pentobarbitone. Less than 1% of a dose is excreted in the urine as unchanged drug. 5-(3-Carboxy-... 

Ketamine, a dissociative anaesthetic, is administered as a racemic mixture (present in the parenteral preparation) and is initially metabolized by the liver to AT-desmethylketamine (metabolite I), which in part is converted by oxidation to the cyclohexene (metabolite II) (Fig. 1.5). The major metabolites found in urine are glucuronide conjugates that are formed subsequent to hydroxylation of the cyclohexanone ring. As the enantiomers differ in anaesthetic potency and the enantioselectively formed (metabolite I has approximately 10% activity of the parent drug) interpretation of the relationship between the anaesthetic effect and disposition of ketamine is complicated. On a pharmacodynamic basis, the S(+) enantiomer is three times as potent as the R(-) enantiomer (Marietta et al., 1977 Deleforge et al., 1991), while the enantiomer that undergoes N-demethylation (hepatic microsomal reaction) differs between species (Delatour et al, 1991). Based on the observed minimum anaesthetic... 

Jones, J.P., Mysinger, M. and Korzekwa, K.R. (2002) Computational models for cytochrome P450 a predictive electronic model for aromatic oxidation and hydrogen atom abstraction. Drug Metabolism and Disposition The Biological Fate of Chemicals, 30, 7-12. 

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