The currently available drugs for the treatment of systemic fungal infections are amphotericin B, flucytosine, miconazole and ketoconazole.Amphotericin B has to be given intravenously in the treatment of deep mycoses. The dose is gradually increased following a small initial dose, though this may delay the attainment of therapeutic concentrations. Amphotericin B serum concentrations are proportional to dose but only up to doses of 50mg. The serum pharmacokinetics fit a 3-compartment model, while cerebrospinal fluid pharmacokinetics fit a 2-compartment model. The precise identities of these compartments have not been determined. In the serum there is a relatively rapid initial half-life of 1 to 2 days, and a slower elimination phase of 15 days. Amphotericin B penetrates poorly into other body tissues, and concentrations are usually well below those in serum. This may partly be due to its high protein binding. The routes of amphotericin B elimination in man are unknown. Amphotericin B invariably causes dose-related renal damage, but this does not markedly alter its pharmacokinetics; mannitol infusions do not reduce this nephrotoxicity. Concurrent gentamicin administration and sodium depletion may enhance amphotericin B nephrotoxicity.Flucytosine may be given orally or intravenously. It has a high (greater than 80%) oral bioavailability, but this is lower in patients with renal failure. Flucytosine absorption is delayed in renal failure and by antacids. The serum pharmacokinetics fit a I-compartment model, and the apparent volume of distribution approximates to body water. Flucytosine has low protein binding and good tissue penetration. There is minimal metabolism in man; conversion to 5-fluorouracil may be the basis of flucytosine toxicity. Since flucytosine is largely eliminated by renal excretion, serum concentrations are markedly increased in the presence of renal impairment. The renal clearance of flucytosine closely parallels creatinine clearance, and in renal failure the half-life is considerably prolonged. Toxicity can be avoided by therapeutic monitoring of serum concentrations and reducing the dose when renal function is impaired.Miconazole is poorly absorbed from the gut; therefore intravenous administration is required for treatment of systemic fungal infections. Its serum pharmacokinetics fit a 3-compartment model with a short initial half-life of less than 1 hour, an intermediate half-life of 2 hours, and a terminal half-life of 20 hours. Despite this long terminal half-life, miconazole has to be given every 8 hours. It has a high apparent volume of distribution and is highly bound to plasma proteins. Adequate penetration only occurs into certain body tissues. Penetration into cerebrospinal fluid is poor and intrathecal injection may be required. Miconazole is oxidised in man and the inactive metabolites are excreted mainly in urine. Serum concentrations of miconazole are higher in renal failure, but dosage adjustment is rarely necessary. Miconazole toxicity is not related to pharmacokinetics, and the need for therapeutic monitoring of serum concentrations is unclear. Miconazole enhances the anticoagulant effect of warfarin.Ketoconazole is well absorbed from the gut. Food has been reported to both enhance and reduce ketoconazole absorption. Absorption is decreased in renal failure and when gastric acidity is reduced. Its pharmacokinetics fit a 2-compartment model. The initial half-life is between 1 and 4 hours and the terminal half-life ranges between 6 and 10 hours; both elimination phases are dose-dependent. Ketoconazole is almost completely protein bound, and penetration into body tissues is variable. It is extensively metabolised, mainly by oxidation, to metabolites without antifungal activity which are excreted in urine and faeces. Renal and hepatic disease do not appear to affect ketoconazole kinetics. Therapeutic failure is associated with low serum concentrations of the drug, therefore therapeutic monitoring is of use in such patients. Cimetidine, and presumably other H2-receptor antagonists, reduce ketoconazole serum concentrations by reducing absorption.