CYP3A4 isoenzyme

P450 system Sirolimus is extensively metabolized by the CYP3A4 isoenzyme in the gut wall and liver. Therefore, absorption and the subsequent elimination of systemically absorbed sirolimus may be influenced by drugs that affect this isoenzyme. Exercise care when concomitantly administering drugs metabolized by CYP3A4 with sirolimus. 

Inhibitors of the CYP3A4 isoenzyme could increase systemic dofetilide exposure. Inhibitors of this isoenzyme (e.g., macrolide antibiotics, azole antifungal agents, protease inhibitors, serotonin reuptake inhibitors, amiodarone, cannabinoids, diltiazem, grapefruit juice, nefazadone, norfloxacin, quinine, and zafirlukast) should be cautiously coadministered with TIKOSYN, because they can potentially increase dofetilide levels... 

Nefazodone is an inhibitor of the CYP3A4 isoenzyme, so it can raise the level and thus exacerbate adverse effects of many 3A4-dependent drugs. For example, triazolam levels are increased by concurrent administration of nefazodone such that a reduction in triazolam dosage by 75% is recommended. Likewise, administration of nefazodone with simvastatin has been associated with 20-fold increase in plasma levels of simvastatin. 

Sildenafil, tadalafil and vardenafil have similar, although not identical, mechanisms of action and structural similarity, and are metabolized primarily by the CYP3A4 isoenzymes, Vardenafil is 32-fold more potent than sildenafil in inhibiting phosphodiesterase type 5. Tadalafil has a quicker onset of action and a longer duration of action - around 36 hours - hence the need to be aware of the potential for adverse drug interactions for nearly 2 days after the intake of a single tablet. 

CALCIUM CHANNEL BLOCKERS IMATINIB t plasma concentrations of imatinib when is co-administered with dilti-azem, nifedipine or verapamil, t risk of toxicity (e.g. abdominal pain, constipation and dyspnoea) and of neurotoxicity (e.g. taste disturbances, dizziness, headache, paraesthesias and peripheral neuropathy) Due to inhibition of hepatic metabolism of imatinib by the CYP3A4 isoenzymes by diltiazem Monitor for clinical efficacy and for the signs of toxicity listed along with convulsions, confusion and signs of oedema (including pulmonary oedema). Monitor electrolytes and liver function, and for cardiotoxicity... 

Paroxetine metabolism at low concentrations is dependent on CYP2D6, which is almost saturated at these concentrations, Thus, there are non-linear pharmacokinetics and an increase in the half-life of paroxetine from 10 to 20 hours when the dose is increased from lOmg to 20mg, At higher concentrations, the metabolism is mainly by CYP3A4 isoenzymes, Paroxetine inhibits the activity of CYP2D6 in the lowest usually effective antidepressant dose,... 

Eletriptan is metabolized mainly by the CYP3A4 isoenzymes and is subject to activity of the P-gp efflux barrier in the brain. 

ST JOHN S WORT CORTICOSTEROIDS 1 plasma concentrations of corticosteroids and risk of poor or inadequate therapeutic response, which would be undesirable if used for e.g. cerebral oedema Due to induction of the hepatic metabolism by the CYP3A4 isoenzymes Monitor therapeutic response closely -clinically, with ophthalmoscopy and radiologically - and t dose of corticosteroids for desired therapeutic effect... 

ALMOTRIPTAN, ELETRIPTAN MACROLIDES -CLARITHROMYCIN, ERYTHROMYCIN, TELITHROMYCIN t plasma concentrations of almotriptan and eletriptan, with risk of toxic effects, e.g. flushing, sensations of tingling, heat, heaviness, pressure or tightness of any part of body including the throat and chest, dizziness Almotriptan is metabolized mainly by CYP3A4 isoenzymes. Most CYP isoenzymes are inhibited by clarithromycin to varying degrees, and since there is an alternative pathway of metabolism by MAO-A, toxicity responses will vary between individuals Avoid co-administration... 

ALMOTRIPTAN RIFAMPICIN Possible 1 plasma concentrations of almotriptan, with risk of inadequate therapeutic efficacy One of the major metabolizing enzymes of almotriptan - CYP3A4 isoenzymes - are induced by rifampicin. As there are alternative metabolic pathways, the effect may not be significant and can vaiy from individual to individual Be aware of the possibility of 1 response to triptan, and consider t of dose if considered to be due to interaction... 

IMATINIB DOXORUBICIN t risk of myelosuppression due to t plasma concentrations Due to 1 metabolism of doxorubicin by CYP3A4 isoenzymes owing to inhibition of those enzymes Monitor for t myelosuppression, peripheral neuropathy, myalgias and fatigue... 

TOREMIFENE ANTIBIOTICS -MACROLIDES T plasma concentrations of toremifene with clarithromycin and erythromycin Due to inhibition of metabolism of toremifene by the CYP3A4 isoenzymes by clarithromycin Clinical relevance is uncertain. Necessaiy to monitor for clinical toxicities... 

IL-2 PROTEASE INHIBITORS t protease inhibitor levels, with risk of toxicity Aldesleukin induces formation of IL-6, which inhibits the metabolism of protease inhibitors by the CYP3A4 isoenzymes Warn patients to report symptoms such as nausea, vomiting, flatulence, dizziness and rashes. Monitor blood sugar at initiation of and on discontinuing treatment... 

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