Amphotericin B lipid complex or amphotericin B multiple-dose administration to rabbits with elevated plasma cholesterol levels: Pharmacokinetics in plasma and blood, plasma lipoprotein levels, distribution in tissues, and renal toxicities

The purpose of the present study was to determine if a relationship exists between the plasma cholesterol concentration, the severity of amphotericin B (AmpB)-induced renal toxicity, and the pharmacokinetics of AmpB in plasma in hypercholesterolemic rabbits administered multiple doses of amphoterici n B (AmB) deoxycholate (Doc-AmB) and AmB lipid complex (ABLC), After 7 days of administration of a cholesterol-enriched diet (0.50% [wt/vol]) or a reg ular rabbit diet, each rabbit was administered a single intravenous bolus o f Doc-AmB (n = 8) or ABLC (n = 10) (1.0 mg/kg of body weight) daily for 7 c onsecutive days (a total of eight doses). Blood samples were obtained daily before and 24 h after the administration of each dose and serially thereaf ter following the administration of the last dose for the assessment of pha rmacokinetics in plasma, kidney toxicity, plasma lipoprotein levels, and dr ug distribution in tissue. The pharmacokinetics of AmB in blood following t he administration of ABLC were also determined in rabbits fed cholesterol-e nriched and regular diets (n = 3 each group). Before drug treatment, choles terol-fed rabbits demonstrated marked increases in total, low-density lipop rotein (LDL), and triglyceride-rich lipoprotein (TRL) cholesterol levels in plasma compared with the levels in rabbits on a regular diet. No significa nt differences in total plasma triglyceride levels were observed. Significa nt increases in plasma creatinine levels were observed in rabbits fed a cho lesterol-enriched diet (P < 0.05) and rabbits fed a regular diet (P < 0.05) when administered AmB, However, the magnitude of this increase was twofold greater in rabbits fed a regular diet than in rabbits fed a cholesterol-en riched diet. An increase in plasma creatinine levels was observed only in r abbits on a cholesterol-enriched diet administered ABLC, The pharmacokineti cs of AmB were significantly altered in rabbits on a cholesterol-enriched d iet administered Doc-AmB or ABLC compared to those in rabbits on a regular diet administered each of these compounds, The pharmacokinetics of AmB in b lood were significantly different following ABLC administration but not fol lowing Doc-AmB administration in both rabbits fed cholesterol-enriched diet s and rabbits fed regular diets compared to their corresponding pharmacokin etics in plasma. An increased percentage of AmB was recovered in the TRL fr action when Doc-AmB was administered to rabbits fed a cholesterol-enriched diet than when it was administered to rabbits fed a regular diet. Furthermo re, an increased percentage of AmB was recovered in the LDL and TRL fractio ns when ABLC was administered to rabbits fed a cholesterol-enriched diet ra bbits fed a regular diet. These findings suggest that an increase in plasma cholesterol levels modifies the pharmacokinetics of AmB and renal toxicity following the administration of multiple intravenous doses of Doc-AmB and ABLC.