Pharmacokinetics, tissue distribution, and toxicity of free and liposomal amphotericin B in diabetic rats.

Abstract

The pharmacokinetics, tissue distribution, and toxicity of free amphotericin B (free AmB) or amphotericin B encapsulated in liposomes (L-AmB) were characterized in experimental diabetic rats and compared with data obtained from nondiabetic rats. After 7 days of insulin-controlled diabetes or saline, each rat was administered a single intravenous bolus dose of free AmB or L-AmB (0.8 mg/kg body weight). Blood samples were obtained before administration and serially thereafter for the assessment of serum pharmacokinetics, nephrotoxicity, and biochemical parameters. Before drug treatment, diabetic rats demonstrated marked increases in serum cholesterol and triglyceride levels compared with levels in nondiabetic rats. A significant increase in serum creatinine levels was observed in nondiabetic rats given free AmB but not in other groups. Whereas AmB pharmacokinetics were significantly altered in diabetic rats administered free AmB, no kinetic differences were found between groups given L-AmB. Renal AmB levels were markedly increased in nondiabetic rats given free AmB compared with those in all other groups. Furthermore, significantly greater concentrations of free AmB were found in lung tissue of rats administered L-AmB independent of disease state. Hepatic levels of AmB were reduced in diabetic rats administered free AmB. The disposition and nephrotoxicity of L-AmB were independent of vascular lipid composition.