CYP3A4 isoenzyme inhibition

The drugs that induce cytochrome P-450 system isoenzyme CYP3A4 will inhibit the blood levels of amprenavir. It decreases the plasma levels of methadone and delavirdine and increases the plasma levels of rifabutin, ketoconazole and atorvas-tatin. This may be the result of the ability of amprenavir to inhibit as well as induce CYP3A4. 

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,... 

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... 

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... 

REPAGLINIDE GRAPEFRUIT JUICE Possibly T repaglinide levels Due to inhibition of CYP3A4 isoenzymes, which metabolize repaglinide Uncertain if clinically significant. May need to monitor blood glucose more closely... 

Quinupristin-dalfopristin (combined in a 3 7 ratio) inhibits CYP3A4 isoenzymes. At doses over 10mg/kg, it prolongs the Q-T interval. 

These antifungals are inhibitors of the CYP3A4 isoenzyme but the inhibiting potencies of azoles vary itraconazole and ketoconazole are considered to be more potent than posaconazole and voriconazole, which in turn are more potent than fluconazole. Fluconazole, itraconazole and voriconazole also inhibit CYP2C9 and CYP2C19. 

CLARITHROMYCIN, ERYTHROMYCIN IRINOTECAN t plasma concentrations of SN-38 (>AUC by 100%) and T toxicity of irinotecan, e.g. diarrhoea, acute cholinergic syndrome, interstitial pulmonary disease Due to inhibition of the metabolism of irinotecan by CYP3A4 isoenzymes by macrolides Peripheral blood counts should be checked before each course of treatment. Monitor lung function. Recommendation is to 4 dose of irinotecan by 25%... 

RIFABUTIN VORICONAZOLE t plasma concentrations of rifabutin, with risk of toxic effects of rifabutin (nausea, vomiting). Dangerous toxic effects such as leukopenia and thrombocytopenia may occur Due to inhibition of metabolism of rifabutin by the CYP3A4 isoenzymes by voriconazole Avoid concomitant use. If absolutely necessaiy, close monitoring of FBC and liver enzymes and examination of eyes for uveitis and corneal opacities is necessary... 

FLUCONAZOLE, ITRACONAZOLE, KETOCONAZOLE, POSACONAZOLE, VORICONAZOLE CALCIUM CHANNEL BLOCKERS Plasma concentrations of dihydropyridine calcium channel blockers are t by fluconazole, itraconazole and ketoconazole. Risk of t verapamil levels with ketoconazole and itraconazole. Itraconazole and possibly posaconazole may t diltiazem levels The azoles are potent inhibitors of CYP3A4 isoenzymes, which metabolize calcium channel blockers. They also inhibit CYP2C9-mediated metabolism of verapamil. Ketoconazole and itraconazole both inhibit intestinal P-gp, which may t bioavailability of verapamil. Diltiazem is mainly a substrate of CYP3A5 and CYP3A5P1, which are inhibited by itraconazole. 75% of the metabolism of diltiazem occurs in the liver and the rest in the intestine. Diltiazem is a substrate of P-gp (also an inhibitor but unlikely to be significant at therapeutic doses), which is inhibited by itraconazole, resulting in t bioavailability of diltiazem Monitor PR, BP and ECG, and warn patents to watch for symptoms/signs of heart failure... 

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