Fluconazole metabolism

Black DJ, Kunze KL, Wienkers LC, et al. Warfarin-fluconazole. II.A metabolically based drug interaction in vivo studies. Drug Metab Dispos 1996 24(4) 422-428. 

Due to the metabolic stability, low molecular weight and absence of ionization at physiological pH, fluconazole has to rely on renal clearance as its major clearance mechanism. The compound has a log P or D7 4 value of 0.5, which means following filtration at the glomerulus a substantial proportion (80 %) of the compound in the filtrate will undergo tubular reabsorption. The resultant low rate of renal clearance gives fluconazole a 30-h half-life in man and is consequently suitable for once-a-day administration. 

Fluconazole is an inhibitor of the cytochrome P450 3A4 and 2C9 enzyme systems. Coadministration of fluconazole with other drugs metabolized by the same enzyme system may result in increased plasma concentrations of the drugs, which could increase or prolong therapeutic and adverse effects. Unless otherwise specified, dosage adjustment may be necessary. 

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). 

The importance of these enzymes for drug interactions is that enzyme inducers and inhibitors may preferentially affect certain isoforms and consequently may only affect the metabolism of selected drugs. For example, ketoconazole has the potential to inhibit the metabolism of drugs metabolised to a great extent by the sub-family 3A (e.g. midazolam) but not of those metabolised by sub-family 1A (e.g. theophylline), 2C (e.g. diazepam), or 2D (e.g. metaprolol). In contrast, although fluconazole is a weaker inhibitor of the sub-family 3A than ketoconazole, it also inhibits the sub-family 2C, and so the interactions of fluconazole differ from those of ketoconazole. 

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... 

Nevirapine is a moderate inducer of CYP3A metabolism, resulting in decreased levels of amprenavir, indinavir, lopinavir, saquinavir, efavirenz, and methadone (Table 49-4). Drugs that induce the CYP3A system, such as tipranavir, rifampin, rifabutin, and St. John s wort, can decrease levels of nevirapine, whereas those that inhibit CYP3A activity, such as fluconazole, ketoconazole, and clarithromycin, can increase nevirapine levels. 

Phenytoin [P] Decreased metabolism of phenytoin with fluconazole and probably voriconazole. 

Fluconazole [NE] Decreased metabolism of cisapride possible ventricular arrhythmia. 

Drugs that may inhibit cytochrome P450 metabolism of other drugs include amiodarone, androgens, atazanavir, chloramphenicol, cimetidine, ciprofloxacin, clarithromycin, cyclosporine, delavirdine, diltiazem, diphenhydramine, disulfiram, enoxacin, erythromycin, fluconazole, fluoxetine, fluvoxamine, furanocoumarins (substances in grapefruit juice), indinavir, isoniazid, itraconazole, ketoconazole, metronidazole, mexile-tine, miconazole, nefazodone, omeprazole, paroxetine, propoxyphene, quinidine, ritonavir, sulfamethizole, verapamil, voriconazole, zafirlukast, and zileuton. 

Fluconazole was designed following much earlier work on imidazole derivatives, which had been shown to inhibit a crucial step in biosynthesis of ergosterol, the essential sterol of the fungal membrane. Imidazoles were shown to be poorly effective in vivo because of rapid and extensive metabolism. Note the design features ... 

Sirolimus is metabolized by CYP2A4 and is a substrate of the P-glycoprotein drug efflux pump drugs like voriconazole, itraconazole, fluconazole and erythromycin increase its blood concentration. Conversely, the inducers of CYP3A4 will decrease blood levels of sirolimus. Cyclosporine increases the bioavailability of sirolimus, possibly due to P-GP inhibition and competition for CYP3A4. The bioavailability is more than 30-40% when the two drugs are administered 4 h apart and is more than... 

The effect of fluconazole 150 mg on circulating ethinylestradiol concentrations has been studied on day 6 of one of two cycles in women taking oral contraceptives (343). The serum concentrations of ethinylestradiol (Cmax and AUC) were significantly increased by fluconazole, but tmax was not affected. These findings suggest that there is a potential for a clinically significant interaction between fluconazole and ethinylestradiol, by inhibition of estrogen metabolism. 

In a randomized, double-blind, crossover study in 12 healthy volunteers, fluconazole increased the plasma concentrations of fluvastatin and prolonged its elimination the mechanism was probably inhibition of the CYP2C9-mediated metabolism of fluvastatin (70). Care should be taken if fluconazole or other potent inhibitors of CYP2C9 are given to patients using fluvastatin. 

Mechanism of Action. Itraconazole works like fluconazole and similar azoles. These drugs disrupt membrane function of the fungal cell by inhibiting the synthesis of key membrane components such as sterols, and by directly damaging other membrane components such as phospholipids. Impaired membrane function leads to metabolic abnormalities and subsequent death of the fungal cell. 

Due to prokinetic effects in the colon, abdominal cramps and diarrhea occur in up to 15% of patients taking cisapride however significant problems are unusual. In addition, cisapride is metabolized by the hepatic cytochrome P450 CYP3 A4 enzyme. When coadministered with drugs that inhibit this enzyme (such as ketoconazole, fluconazole, macrolide antibiotics, and HIV protease inhibitors), significant increases in serum levels of cisapride may occur that rarely lead to QT prolongation on the ECG and serious cardiac arrhythmias. For this reason, cisapride was removed... 

Kunze KL, Trager WF. Warfarin-fluconazole. 3. A rational approach to management of a metabolically based drug-interaction. Drug Metab Dispos 1996 24 429-435. 

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