P450 enzyme system

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. 

The experiment was conducted in the presence of the fungus and the compound ABT at sufficiently high concentration, 5 mM, to cause the inhibition of Cyp P450 enzyme system expression by the fungus. 

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. 

Because trimetrexate is metabolized by a P450 enzyme system, drugs that induce or inhibit this drug metabolizing enzyme system may elicit important drug interactions that may alter trimetrexate plasma concentrations, which include erythromycin, rifampin, rifabutin, ketoconazole, fluconazole, cimetidine, nitrogen substituted imidazole drugs (eg, clotrimazole, ketoconazole, miconazole). 

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). 

There is clear evidence of the extensive involvement of the P450 enzyme system in the elimination of pharmaceutical agents and an enormous body of information demonstrating the modulation of activity, via inhibition or induction, with polypharmacy. This fully justifies the intensive research in this area and the pharmaceutical industry s focus on such drug-drug interactions. This focus is reinforced in this volume, in which P450 is either the major or the most significant subject of over half the chapters, and inhibition and induction, in vitro and in vivo, are further exemplified and discussed. 

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... 

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