P450 cytochrome enzyme systems

Another new development of immediate clinical usefulness is the analysis of genetic variability in the cytochrome P450 enzyme system in patients, which... 

Ticlopidine inhibits the P2Yj2 platelet ADP receptor, thus inhibiting ADP-dependent activation of the GP Ilb/IIIa receptor. It has a slow onset of action and takes 3-7 days to reach its maximal antiplatelet effect. It is inactive in vitro and must undergo activation by the hepatic cytochrome p450 enzyme system. Secondary prevention trials have found that ticlopidine-treated patients have an estimated RRR of 33% for the composite endpoint of stroke, myocardial infarction, or vascular death after ischemic stroke. Significant adverse effects include bone marrow depression, rash, diarrhea, and thrombotic thrombocytopenic purpura. No clinical trials have studied ticlopidine for the treatment of stroke in the acute phase. 

Andersson T, L Fortin (1992) Regulation of the cytochrome P450 enzyme system in fish. Aquat Toxicol 24 1-20. 

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... 

St. John s wort is probably effective for mild to moderate but not severe depression. Although well tolerated in most patients, a major concern is its numerous herb-drug interactions mediated by its induction of the cytochrome P450 enzyme system. 

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. 

Such reactions are interesting as models for oxygen atom transfer in mechanisms of dioxygen activation by cytochrome P450 enzyme systems (49, 50, 51). 

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. 

Reimann G, Barthel B, Rockstroh JK, Spatz D, Brockmeyer NH. Effect of fusidic acid on the hepatic cytochrome P450 enzyme system. Int J Clin Pharmacol Ther 1999 37(ll) 562-6. 

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. 

The mixed function oxidases and cytochrome P450 enzyme systems do not play a role in the clearance of macromolecules. Nor do large proteins interact with transporter proteins such as P-gp, despite the fact that one site of clearance is the... 

ADAS-COG Alzheimer s Disease Assessment Scale—Cognition ADRDA Alzheimer s Disease and Related Disorders Association apo E apolipoprotein E APP amyloid precursor protein /SAP beta-amyloid protein CYP450 cytochrome P450 enzyme system DSM-IV-TR Diagnostic and Statistical Manual of Mental Disorders, 4th ed.. Text Revision FAQ functional activities questionnaire MMSE mini-mental status exam NFT neurofibrillary tangle... 

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. 

The five major classes of steroid hormones are derived from cholesterol by the pathway illustrated in Figure 34-2. Hydroxylation is important in these conversions. The hydroxylation reactions require NADPH and and are carried out by the cytochrome P450 enzyme system. The enzyme 21-hydroxylase is required for the synthesis of mineralocorticoids and glucocorticoids. 

Human Hepatic Cytochrome P450 Enzyme System... 

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-... 

Azithromycin is believed to be metabolised by routes independent of the cytochrome P450 enzyme system. Intravenous azithromycin was thought to have increased ciclosporin levels through P-glycoprotein inhibition and/or competition for biliary excretion in one case report. ... 

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