Cytochrome P450 enzyme system metabolism

Metabolism - Repaglinide is completely metabolized by the liver. The cytochrome P450 enzyme system, specifically 3A4, is involved in the N-dealkylation of repaglinide. 

Amprenavir is metabolized by the cytochrome P450 enzyme system and inhibits CYP3A4. Use caution when coadministering medications that are substrates, inhibitors, or inducers of CYP3A4, or potentially toxic medications that are metabolized by CYP3A4. 

Absorption after oral administration is incomplete and variable. Its bioavailability ranges from 20% to 50%. Cyclosporine can also be given intravenously. Plasma protein binding is about 90% and cyclosporine also accumulates in red blood cells. It is extensively metabolized in the gastrointestinal mucosa and in the liver by the cytochrome P450-enzyme system. Its elimination half-life is about 19 hours in adults with a range of 10-27 hours and about 9 hours in children with a range of 3-19 hours. Over 30 different metabolites have been... 

In this chapter, we have discussed the mechanisms of action of the major antidepressant drugs. The acute pharmacological actions of these agents on receptors and enzymes have been described, as well as the major hypothesis that attempts to explain how all current antidepressants ultimately work. That hypothesis is known as the neurotransmitter receptor hypothesis of antidepressant action. We have also introduced pharmacokinetic concepts relating to the metabolism of antidepressants and mood stabilizers by the cytochrome P450 enzyme system. 

Resistance to insecticides can be due to enhanced oxidative metabolism caused by cytochrome P450 monooxygenases. This type of resistance usually results in producing less toxic metabolites. Even when the metabolites are more toxic, often resistance prevails, perhaps because the toxic metabolites are less stable, cannot reach the site of action due to change in polarity, or are neutralized by other factors. As we have already seen (Chapter 8), the cytochrome P450 enzyme system is rather nonspecific in its attack on organic compounds. Hence, this resistance factor is nonspecific, explaining much of the cross-resistance observed. 

Macrolides are metabolized in the liver via the microsomal (cytochrome P450) enzyme system. The alkylxanthines (e.g. theophylline, amino-phylline) utilize the same enzyme system, so concurrent administration with macrolides leads to a doubling of the alkylxanthine concentration and toxicity. Because of similar mechanisms of action, concurrent administration of other macrolides, lincosamides, chloramphenicol or florfenicol is not recommended. 

Cytochrome P450 enzyme system The cytochromes P450 are mixed-function oxidases that require both NADPH and O. They are involved in a number of reactions in the conversion of lanosterol to cholesterol, as well as important steps in the synthesis of steroid hormones. Cytochromes P450 are very important in the detoxification of xenobiotics and in the metabolism of drags. 

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. ... 

The reasons for this interaction are not understood, but among the suggestions are that the itraconazole inhibits the metabolism of vincristine by the cytochrome P450 enzyme system, so that it is cleared from the body less quickly. Another possible explanation is that itraconazole inhibits P-glycoprotein, and increased vincristine neurotoxicity may be the result of the inhibition of this pump in endothelial cells of the blood-brain barri-... 

In the cases where rhabdomyolysis developed when clopidogrel was added to treatment with eielosporin and a statin it was thought that the addition of clopidogrel (which may also inhibit the cytochrome P450 enzyme system) may have destabilised the delicate metabolic equilibrium between the statins and eielosporin precipitating the development of rhabdomyolysis. 

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). 

Measure toxic effects in the target cell expressing the cytochrome P450 enzyme. This approach is inherently more sensitive than use of extracellular metabolism systems or coculture approaches. Therefore one is more likely to observe an effect at physiological exposure concentrations. 

The cDNA expression systems can be used to address questions such as can human enzymes metabolize a xenobiotic What are the metabolites Can human enzymes activate a protoxin In order to adequately support a negative conclusion it is obvious that the range of cytochrome P450 enzymes examined needs to be as comprehensive as possible. 

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