Pharmacokinetics, Tissue Distribution, and Toxicity of Free and Liposomal Amphotericin B in Diabetic Rats

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Abstract
The pharmacokinetics, tissue distribution, and toxicity of free amphotericin B (free AmB)or amphotericin Bencapsulated in liposomes(L-AmB) werecharacterized 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 (0.8mg/kg body weight). Bloodsamples wereobtained beforeadministration and serially thereafter for the assessment of serum pharmacokinetics, nephrotoxicity, and biochemical parameters. Beforedrug treatment, diabetic rats demonstrated marked increases in serum cholesterol and triglyceride levels compared with levelsin 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 diabeticrats administered freeAmB, no kinetic differences were found between groups givenL-AmB. Renal AmB levels we remarkedly increased in nondiabetic rats given freeAmBcompared 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 levelsof AmB were reduced in diabetic rats administered freeAmB.The disposition and nephrotoxicity of L-AmB were independent of vascular lipid composition.