Oxidative metabolites formation

Bodor, N. Buchwald, P. (2006) Designing Safer (Soft) Drugs by Avoiding the Formation of Toxic and Oxidative Metabolites. Molecular Biotechnology, 26(2), 123-132. 

Prevents formation of hydroxylamine (oxidizing) metabolite of dapsone... 

Ring, B. J. et al. (1996). Identification of the human cytochromes P450 responsible for the in vitro formation of the major oxidative metabolites of the antipsychotic agent olanzapine. /. Pharmacol. Exp. Ther., 276, 658-66. 

Screening is usually carried out with liver microsomes from humans, rats, mice, dogs and monkeys and liver S9 fraction from aroclor 1254-induced rats. The incubation is typically mn with a volume of 0.2-1. OmL in a microcentrifuge or a glass tube. Different incubation conditions are used for CYP and UGT reactions. The incubation mixture for formation of oxidative metabolites and/or GSH conjugates contains ... 

Ortiz de Montellano PR, Komives EA. Branchpoint for heme alkylation and metabolite formation in the oxidation of arylacetylenes by cytochrome P-450. J Biol Chem 1985 260(6) 3330-3336. 

Mansuy D, Valadon P, Erdelmeier I, et al. Thiophene S-oxides as new reactive metabolites formation by cytochrome P450 dependent oxidation and reaction with nucleophiles. J Am Chem Soc 1991 113(20) 7825—7826. 

Metabolism - Following a 400 mg dose of C-indinavir, 83% and 19% of the total radioactivity was recovered in feces and urine, respectively radioactivity caused by parent drug in feces and urine was 19.1% and 9.4%, respectively. Seven metabolites have been identified 1 glucuronide conjugate and 6 oxidative metabolites. In vitro studies indicate that cytochrome P450 3A4 (CYP3A4) is the major enzyme responsible for formation of the oxidative metabolites. 

As already discussed in chapter 4, reactive intermediates can react with reduced GSH either by a direct chemical reaction or by a GSH transferase-mediated reaction. If excessive, these reactions can deplete the cellular GSH. Also, reactive metabolites can oxidize GSH and other thiol groups such as those in proteins and thereby cause a change in thiol status. When the rate of oxidation of GSH exceeds the capacity of GSH reductase, then oxidized glutathione (GSSG) is actively transported out of the cell and thereby lost. Thus, reduced GSH may be removed reversibly by oxidation or formation of mixed disulfides with proteins and irreversibly by conjugation or loss of the oxidized form from the cell. Thus, after exposure of cells to quinones such as menadione, which cause oxidative stress, GSH conjugates, mixed disulfides, and GSSG are formed, all of which will reduce the cellular GSH level. 

Bodor, N., and Buchwald, P. Designing safer (soft) drugs by avoiding the formation of toxic and oxidative metabolites. Mol. Biotechnol. 26(2) 123-132, 2004. 

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