Cytochrome P450 enzymes reductive metabolism

All SSRIs (e.g., Feonard et ah, 1997) and in particular fluoxetine, Fluvosamine and paroxetine are metabolized by hepatic cytochrome P450 enzymes. Therefore, it is important to be aware of the possibility that the therapeutic or toxic effects of other medications metabolized by the cytochrome P450 isoenzyme system can be increased. Substantial inhibition of these isoenzymes converts a normal metabolizer into a slow metabolizer with regard to this specific pathway. Inhibition of the hepatic oxidative isoenzymes has been associated with a reduction, to a varying extent, in the clearance of many therapeutic agents, including the TCAs, several neuroleptics, antiarrhythmics, theophy-lene, terfenadine, benzodiazepines, carbamazepine, and warfarin (for a complete list, see Nemeroff et ak, 1996). 

Patients with hepatic insufficiency may not tolerate the drug at usual doses, however, because of increased area under the concentration curve of both parent drugs and metabolites. This may necessitate a dose reduction to 7.5 mg/kg every 12 hours or 5 mg/kg every 8 hours in some patients. Quinupristin and dalfopristin are not metabolized by cytochrome P450 enzymes but significantly inhibit CYP 3 A4, which metabolizes warfarin, diazepam, astemizole, terfenadine, cisapride, nonnucleo- side reverse transcriptase inhibitors, and cyclosporine, among others. Dosage reduction of cyclosporine may be necessary. 

Non-cytochrome P450 enzymes may also be involved in oxidative reactions. One such enzyme is alcohol dehydrogenase whose substrates include vitamin A, ethanol, and ethylene glycol. Aldehyde dehydrogenase is another enzyme. Most reduction reactions also involve microsomal enzymes, with the exception of ketone reduction. Nitro compounds are reduced to amines and volatile anesthetics undergo dehalo-genation by microsomal enzymes. Hydrolysis reactions are involved in metabolism of compounds with amide bonds or ester linkages, as in the conversion of aspirin to salicylate (Brown, 2001). 

Drug metabolism occurs primarily in the liver and most commonly involves oxidation, reduction, hydrolysis, and conjugation reactions. Quantitatively, the most important hepatic enzymes are the cytochrome P450 enzymes that have been divided into families and subfamilies (e.g., CYP3A4) based on the similarity of their amino acid sequences. These enzymes are responsible for the metabolism of a large number of drugs. 

Linezolid is not metabolised by the cytochrome P450 enzyme system so the reduction in levels is unlikely to be due to increased metabolism associated with rifampicin enzyme induction. The reduction in linezolid serum levels may be attributable to the induction of P-glycoprotein by rifampicin, resulting in increased excretion of linezolid. ... 

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. 

Phase I metabolic reactions involve oxidation, reduction, or hydrolysis of the parent molecule, resulting in the formation of a more polar compound. Phase 1 reactions are mediated by the cytochrome P450 (GYP) family of enzymes. While metabolism used to be thought of as the body s detoxification process, phase I metabolites may be equally or even more pharmacologically active than the parent compound. Drug metabolism in general, and CYP-based mechanisms in particular, are discussed in detail in Chapter 5. 

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