Cytochrome P450 enzymes inhibition

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. 

This interceptor theory does not seem to be the only protective mechanism in operation. Inhibition of cytochrome P450 enzymes related to the bioactivation of mutagens and toxic radical scavenger activities have been proposed to integrate the different modes of action. Other investigations have reported the involvement of chlorophyUin in inducing apoptosis in human colon cells, which may be important in limiting cancer cell invasion and metastasis. ... 

Ketoconazole inhibits a variety of cytochrome P450 enzymes, including 11-hydroxylase and 17-hydroxylase. It is highly effective in lowering cortisol in Cushing s disease, and patients can be maintained successfully on therapy for months to years. The most common adverse effects are reversible elevation of hepatic transaminases and GI upset. It can cause gynecomastia and lower plasma testosterone values. 

Testino, A.S., Jr. and Patonay, G. 2003. High-throughput inhibition screening of major human cytochrome P450 enzymes using an in vitro cocktail and liquid chromatography/tandem mass spectrometry. J. Pharm. Biomed. Anal. 30 1459. 

Correia MA, Ortiz de Montellao PR. Inhibition of cytochrome P450 enzymes. In Ortiz de Montellano PR, ed. Cytochrome P450 Structure, Mechanism, and Biochemistry. 3rd ed. New York Kluwer/Plenum 2005 247-322. 

Lin, J.H. and Lu, A.Y. (2001) Interindividual variability in inhibition and induction of cytochrome P450 enzymes. Annual Review of Pharmacology and Toxicology, 41, 535—567. 

Atkinson, A., Kenny, J.R. and Grime, K. (2005) Automated assessment of time-dependent inhibition of human cytochrome P450 enzymes using liquid chromatography-tandem mass spectrometry analysis. Drug Metabolism and Disposition, 33 (11), 1637—1647. 

Taavitsainen P, Juvonen R, Pelkonen O (2001) In vitro inhibition of cytochrome P450 enzymes in human liver microsomes by a potent CYP2A6 inhibitor, trans-2-phenylcyclopropylamine (tranylcypromine), and its nonamine analog, cyclopropylbenzene. Drug Metab Dispos 29(3) 217-222... 

The cytochrome P450 enzymes are responsible for the metabolism of a number of pharmacological agents. Inhibition of these enzymes could result in elevation of serum levels of agents that are dependent on the activity of P450 enzymes for metabolism. 

Liu Y, Zhang IW, Li W et al (2006) Ginsenoside metabohtes, rather than naturally occurring ginsenosides, lead to inhibition of human cytochrome P450 enzymes. 1 Toxicol Sd 91 356-364... 

Higher throughput screening with human cytochrome P450 to study P450-medi-ated metabolism is now available [38-40]. Similarly, rapid microhtre plate assays to conduct for example, P450 enzyme inhibition studies have been developed, using individually expressed CYP enzymes (Supersomes) [41]. 

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. 

Some selective serotonin re-uptake inhibitors are powerful inhibitors of cytochrome P450 enzymes and the metabolism of e.g. tricyclic antidepressants can be inhibited resulting in serious toxicity. Additive sedation can be expected when given in combination with CNS depressants such as benzodiazepines but also with alcohol. Selective serotonin re-uptake inhibitors should not be used in combination with monoamine oxidase inhibitors as fatal reactions have been reported. 

Isoniazid inhibits cytochrome P450 enzyme function and thus can interact with drugs that are subject to cytochrome P450 mediated metabolism like warfarin and the antiepileptic agents phenytoin and car-bamazepine. 

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). 

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