Fluconazole excretion

Metaboiism/Excretion - Fluconazole is cleared primarily by renal excretion, with approximately 80% of the dose appearing in the urine unchanged, approximately 11% as metabolites. The dose may need to be reduced in patients with impaired renal function. A 3-hour hemodialysis session decreases plasma concentrations by approximately 50%. 

Although fosfluconazole is some 25-fold less active than fluconazole in vitro, it is rapidly hydrolyzed by phosphatases in vivo and has similar efficacy in animal models and in patients, where it is 97% bioavailable (Hegde and Schmidt, 2005). The prodrug has a half-life of 2.3 h in patients, and the vast majority of the dose is excreted as fluconazole. Consequently, fosfluconazole has a similar clinical profile to that of fluconazole. 

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... 

Fluconazole is mainly excreted unchanged in the urine and is thus not under the influence of the induction or inhibition of a metabolic pathway. Itraconazole is predominantly metabolized by CYP3A4 and is the only azole with an active metabolite. Itraconazole is also a substrate of P-gp and an inhibitor of P-gp activity. 

ABSORPTION, DISTRIBUTION, AND EXCRETION Fluconazole is almost completely absorbed from the G1 tract irrespective of food or gastric acidity. Only 10% of drug in circulation is protein bound. Renal excretion accounts for >90% of elimination, with a of 25 hours. Fluconazole readily diffuses into body fluids, including breast milk, sputum, saliva, and CSF. The dosage interval should be increased from 24-48 hours for a creatinine clearance of 21 0 mL/min and to 72 hours at 10-20 mL/min. In renal failure, a dose of 100-200 mg is given after hemodialysis. 

Rifabutin increases the metabolism of itraconazole, posaconazole and voriconazole, probably, at least in part, by inducing their metabolism by the cytochrome P450 CYP3A subfamily. Fluconazole is largely excreted unchanged in the urine and so it is not affected. The azoles apparently increase rifabutin levels by inhibiting its metabolism, probably by CYP3A4. Raised rifabutin levels can cause uveitis. 

Rifampicin increases the metabolism of the azote antifungals by the liver. However, as fluconazole (unlike ketoconazole, itraconazole and voriconazole) is mainly excreted unchanged in the urine, changes to its metabolism would not be expected to have as marked an etfect as on these other azotes. 

Only 11% of a dose is metabolised, with 6.5% being a glucirronide conjugate and 2% an N-oxide. The major route of elimination for fluconazole and its metabolites is renal excretion, with only 2% being excreted in the faeces. 

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