Pharmacokinetics of fluconazole and fosfluconazole after intraperitoneal administration to peritoneal dialysis rats.
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 were 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 was administered intravenously and intraperitoneally. After the i.p. administration of F-FLCZ, FLCZ was detected in circulating blood and the dialyzing fluid in peritoneal dialysis rats. The concentration of plasma FLCZ after the i.p. F-FLCZ administration was 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 were analyzed using a two-compartment model in which the distribution volume of the peripheral compartment was 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.
Aoyama
Takahiko
T
Department of Clinical Pharmacology and Toxicology, Showa Pharmaceutical University, Tokyo, Japan.
Ogata
Kazuhiro
K
Shimizu
Makiko
M
Hatta
Shigeo
S
Masuhara
Keiso
K
Shima
Yoshinori
Y
Kimura
Kenjirou
K
Matsumoto
Yoshiaki
Y
D058186:Acute Kidney Injury / Q000378:metabolism; D000465:Algorithms; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D003627:Data Interpretation, Statistical; D015725:Fluconazole / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D008297:Male; D010755:Organophosphates / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010531:Peritoneal Dialysis, Continuous Ambulatory; D051381:Rats; D017208:Rats, Wistar
D000935:Antifungal Agents; D010755:Organophosphates; C486878:fosfluconazole; D015725:Fluconazole; D000469:Alkaline Phosphatase