Pharmacokinetic evaluation of UK-49,858, a metabolically stable triazole antifungal drug, in animals and humans

Abstract

The pharmacokinetic profile of UK-49,858 (fluconazole), a novel triazole antifungal agent which is being developed for oral and intravenous use, was determined in mice, rats, dogs, and humans. Comparative data following oral and intravenous administration showed that bioavailability was essentially complete in all four species. Peak concentrations in plasma of drug normalized to a 1-mg/kg dose level following oral administration, were relatively high: 0.7, 0.6, 1.1, and 1.4 ,ug/ml in mice, rats, dogs, and humans, respectively. UK-49,858 [2-(2,4,-difluorophenyl)-1,3-bis(lH-1,2,4-triazol-1-yl)propan-2-ol; fluconazole; Fig. 1] is a new systemically acting antifungal agent which has shown activity in several animal models of infection (14; P. F. Troke, R. J. Andrews, K. W. Brammer, M. S. Marriott, and K. Richardson, Antimicrob. Agents Chemother., submitted for publication). Typical oral 50% protective dose values against acute lethal systemic candidiasis in mice range between 0.1 and 0.3 mg/kg, demonstrating that the compound is between 20-and 100-fold more potent than ketoconazole in this model. Results of several studies with imidazole antifungal agents have shown that the pharmacokinetics of these compounds have a significant impact on their comparative efficacy in vivo. The pharmacokinetic profiles of such imidazole antifungal agents as miconazole (3, 12), econazole (13), and clotrimazole (7, 15) were characterized by poor oral bioavailability and low plasma concentrations due to significant first-pass metabolism and a large volume of distribution. The recent introduction of ketoconazole (1) has seen the advent of imidazole antifungal drugs with good systemic bioavailability and relatively high plasma concentrations. However, in common with previous imidazoles, ketoconazole is highly bound to plasma proteins (4, 11), is extensively metabolized (9), and exhibits dose-dependent kinetics in both animals (1) and humans (2, 5). This report describes the pharmacokinetic profile of the bistriazole UK-49,858, which is markedly different from that of ketoconazole and related imidazoles and assesses the potential contribution of this profile to the efficacy of the drug in vivo. MATERIALS AND METHODS

Effects of amphotericin B and fluconazole on the extracellular and intracellular growth of Candida albicans

“…This is in agreement with the observations of other investigators (16,28,32,37,38). Since protein binding is reported to be low for Flu (1,14,17), the effect of serum on its antifungal activity was not tested.…”

Has the era of individualised medicine arrived for antifungals? A review of antifungal pharmacogenomics

“…formulations, the oral bioavailability of fluconazole exceeds 90%, 39 and is unaffected by gastric pH, 40 food intake or gastrointestinal disease. 41 It is hydrophilic with minimal protein binding and therefore achieves good tissue penetration into cerebrospinal fluid, saliva, sputum, vagina, skin 41 and brain tissue.…”

Effect of Multiple Oral Dosing of Fluconazole on the Pharmacokinetics of Cyclosporine in Healthy Beagles

“…The washout times after each treatment were >14 days. In this study, we selected 14 days as the washout period because of the half-life (t 1/2 ) of the drugs and on the basis of the results of other studies in which the washout period ranged from 7 to 14 days [2,7,14,29].…”

“…In human liver transplant patients, antifungal prophylaxis with fluconazole (Fcz) significantly reduces the incidence of invasive fungal infections [25]. Fcz penetrates the blood-brain, blood-prostate and blood-ocular barriers, and high concentrations are found in cerebrospinal fluid, urine and ocular fluids [14,31]. Fcz shows efficacy against aspergillosis, candidiasis, coccidioidomycosis, cryptococcosis and histoplasmosis in animal models [10,13,26].…”