Itraconazole metabolism

Voriconazole is the newest triazole to be licensed in the USA. It is available in intravenous and oral formulations. The recommended dosage is 400 mg/d. The drug is well absorbed orally, with a bioavailability exceeding 90%, and exhibits less protein binding than itraconazole. Metabolism is predominantly hepatic, but the propensity for inhibition of mammalian P450 appears to be low. Observed toxicities include rash, elevated hepatic enzymes, and transient visual disturbances. 

Theoretically buprenorphine metabolism could be inhibited by itraconazole, ketoconazole, grapefruit juice, and erythromycin or any other CYP3A4 inhibitor the effects may be greater than expected for the dose of buprenorphine being given may need to decrease buprenorphine dose. 

Drug interactions Metabolized by CYP450 3A4 (e.g., cyclosporine, erythromycin, itraconazole, phenytoin, St. John s wort)... 

Concurrent use with ketoconazole, itraconazole, and nefazodone, medications that significantly impair the oxidative metabolism of triazolam mediated by cytochrome P-450 3A (CYP3A). 

Metabollsm/Excretion— Itraconazole is metabolized by the cytochrome P450 3A4 to several metabolites including the major metabolite hydroxyitraconazole. Fecal excretion of the parent drug varies between 3% and 18% of the dose. Renal excretion of the parent drug is less than 0.03% of the dose. Itraconazole is not removed by hemodialysis. 

Both itraconazole and its major metabolite, hydroxyitraconazole, are inhibitors of the cytochrome P450 3A4 enzyme system. Coadministration of itraconazole and drugs primarily metabolized by the cytochrome P450 3A4 enzyme system may result in increased plasma concentrations of the drugs that could increase or prolong therapeutic and adverse effects. 

As a consequence of its high lipophilicity and low aqueous solubility, gastric acidity is also required for itraconazole absorption (Haria et al., 1996). It is best absorbed when administered with food, although there is considerable interpatient variabihty. The oral bioavailability or itraconazole from a 100-mg solution dose was 55%. Like ketoconazole, its bioavailability and half-life are dose-dependent, indicating saturable metabolism. Once absorbed, itraconazole is highly plasma protein bound (99.8%) and widely distributed (10.7 L/kg). Although itraconazole is widely metabolized, it does produce an active metabolite by hydroxylation of the triazolone side-chain. 

E. Simvastatin. Itraconazole inhibits cytochrome P450 3A4. This cytochrome is responsible for metabolism of simvastatin. Therefore, itraconazole can increase serum level of simvastatin and increase its toxicity. 

Although itraconazole and fluconazole are both triazoles, they are chemically and pharmacologically distinct. Itraconazole (Sporanox) is lipophilic and water insoluble and requires a low gastric pH for absorption. Oral bioavailability is variable, only 50 to 60% when taken with food and 20% or less when the drug is taken on an empty stomach. Itraconazole is highly protein bound (99%) and is metabolized in the liver and excreted into the bile. With initial dosing, the plasma half-life is 15 to 20 hours steady-state serum concentrations are reached only after 2 weeks of therapy, when the half-life is extended to 30 to 35 hours. In lipophilic tissues, drug concentration is 2 to 20 times that found in... 

Itraconazole has significant interactions with a number of commonly prescribed drugs, such as rifampin, phenytoin, and carbamazepine. Itraconazole raises serum digoxin and cyclosporine levels and may affect the metabolism of oral hypoglycemic agents and coumadin. Absorption of itraconazole is impaired by antacids, Hj blockers, proton pump inhibitors, and drugs that contain buffers, such as the antiretroviral agent didanosine. 

Itraconazole contraindicated in patients with evidence of ventricular dysfunction (CHF) or a history of CHF Itraconazole is also a potent inhibitor of cytochrome P450 3A4 isoenzyme, which may increase plasma concentrations of drugs metabolized by this pathway. Serious cardiovascular events have occurred in patients taking cisapride, pimozide, levomethadyl, or quinidine concomitantly with itraconazole. 

With the important exception of additive effects when combined with other CNS depressants, including alcohol, BZDs interact with very few drugs. Disulfiram (see the section The Alcoholic Patient in Chapter 14) and cimetidine may increase BZD blood levels, and diazepam may increase blood levels of digoxin and phenytoin. Antacids may reduce the clinical effects of clorazepate by hindering its biotransformation to desmethyidiazepam. Coadministration of a BZD and another drug known to induce seizures may possibly increase seizure risk, especially if the BZD is abruptly withdrawn. Furthermore, as noted earlier, important interactions have been reported among nefazodone, erythromycin, troleandomycin, and other macrolide antibiotics, as well as itraconazole. In each case, metabolism is inhibited, and triazolam levels can increase significantly. 

Although specific drug or food interactions with mifepristone have not been studied, on the basis of this drug s metabolism by CYP3A4, it is possible that ketoconazole, itraconazole, erythromycin, and grapefruit juice may inhibit its metabolism (increasing serum levels of mifepristone). Furthermore, rifampin, dexamethasone, St. John s wort, and certain anticonvulsants (e.g., phenytoin, phenobarbital, and carbamazepine) may induce mifepristone metabolism (lowering serum levels of mifepristone)... 

The risk of myopathy appears to be increased by high levels of HMG-CoA reductase inhibitory activity in plasma. Lovastatin is metabolized by the CYP isoform 3A4. Certain drugs, that share this metabolic pathway can raise the plasma levels of lovastatin and may increase the risk of myopathy. These include cyclosporine, itraconazole, ketoconazole and other antifungal azoles, the macrolide antibiotics erythromycin and clarithromycin, HIV protease inhibitors, the antidepressant nefazodone, or large quantities of grapefruit juice (greater than 1 quart daily)... 

On the basis of the metabolism of bexarotene by CYP3A4, ketoconazole, itraconazole, erythromycin, gemfibrozil, grapefruit juice, and other inhibitors of CYP3A4 would be expected to lead to an increase in plasma bexarotene concentrations... 

Barbiturates [P] Increased metabolism of itraconazole, ketoconazole, voriconazole. 

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