Fosfluconazole is a prodrug of Fluconazole that is widely used as an antifungal agent.
To investigate the polarized bioconversion and the Transwell transport of phosphate prodrugs in Caco-2 monolayer, 10 μM Fosfluconazole or Fosphenytoin is dosed either in the apical or basal compartment in Transwell plates. Both prodrugs are efficiently cleaved in the apical compartment after a 2 h incubation. To further investigate the kinetics of ALP-mediated bioconversion, the concentration-dependent ALP-mediated bioconversions are conducted to determine the Michaelis-Menten constant (Km) of prodrug bioconversion in Caco-2 monolayers. The saturation curves of Fosphenytoin and Fosfluconazole with the concentration increase are found. The estimated Km values of Fosphenytoin and Fosfluconazole are 1160 and 357 μM, respectively[2].
The apparent half-life for Fosfluconazole bioconversion in intestinal mucosa scraps is 10 min[2]. Fluconazole (FLCZ) is an antifungal agent that is efficacious in the treatment of fungal peritonitis. Fosfluconazole (F-FLCZ) is the phosphate prodrug of FLCZ, which is highly soluble compared with FLCZ. F-FLCZ is useful against fungal peritonitis in continuous ambulatory peritoneal dialysis (CAPD) patients because it has a high water solubility. The aims of the present study are to characterize the peritoneal permeability of FLCZ and the pharmacokinetics of FLCZ and F-FLCZ after intraperitoneal (i.p.) administration to peritoneal dialysis rats. FLCZ or F-FLCZ is administered intravenously and intraperitoneally. After the i.p. administration of F-FLCZ, FLCZ is detected in circulating blood and the dialyzing fluid in peritoneal dialysis rats. The concentration of plasma FLCZ after the i.p. F-FLCZ administration is lower than that after the intravenous (i.v.) F-FLCZ administration. It is considered that the dose should be increased appropriately when F-FLCZ is administered intraperitoneally. The profiles of plasma FLCZ after i.v. and i.p. administrations are analyzed using a two-compartment model in which the distribution volume of the peripheral compartment is fixed at a volume of the dialyzing fluid (peritoneal dialysis PK model). The peritoneal dialysis PK model could describe the profiles of plasma and dialyzing fluid FLCZ. These results suggest that FLCZ and F-FLCZ could be administered intraperitoneally for the treatment of fungal peritonitis in CAPD patients[3].
[1]. Hagiya H, et al. Successful treatment of recurrent candidemia due to candidal thrombophlebitis associated with a central venous catheter using a combination of Fosfluconazole and micafungin. Intern Med. 2013;52(18):2139-43. [2]. Yuan H, et al. Evaluation of in vitro models for screening alkaline phosphatase-mediated bioconversion of phosphate ester prodrugs. Drug Metab Dispos. 2009 Jul;37(7):1443-7. [3]. Aoyama T, et al. Pharmacokinetics of fluconazole and Fosfluconazole after intraperitoneal administration to peritoneal dialysis rats. Drug Metab Pharmacokinet. 2005 Dec;20(6):485-90.