Pharmacokinetics and Renal Toxicity of Monomeric Amphotericin B in Rats after a Multiple Dose Regimen.

Background: Delivery of monomeric Amphotericin B (AmB), i.e. deaggregated AmB, has been a major tactic in the reduction of renal toxicity at a membrane level, taking advantage of the selectivity of monomeric AmB for binding ergosterol over cholesterol.

Objective: The aim of this study was to characterize the pharmacokinetic (PK) and renal toxicity of monomeric AmB in rats following a multiple dose regimen.

Method: AmB existed primarily in a monomeric state in poly(ethylene glycol)--poly(N-hexyl stearate L-aspartamide) (PEG--PHSA) micelles (mAmB) at 2:1 ratio (mol:mol), whereas AmB as its standard formulation, Fungizone, was highly self-aggregated based on absorption spectroscopy.

Results: After single intravenous injection, mAmB significantly (p < 0.001) increased the area under the plasma drug concentration-time curve (AUC) and reduced the volume of distribution (V) and total systemic clearance (CL) relative to Fungizone. After daily intravenous injections at dose of 1.0 mg/kg for 7 days, PK parameters of mAmB and Fungizone were similar to day 1. The treatment of Fungizone also significantly (p < 0.05) increased levels of urinary enzymes, N-acetyl-β-D-glucosaminidase (NAG) and kidney injury molecule-1 (KIM-1) by 3.1- and 3.0 fold, respectively, whereas levels of NAG and KIM-1 were unchanged for mAmB, consistent with hematoxylin and eosin (H&E) staining of excised kidneys.

Conclusion: In summary, mAmB has less renal toxicity than AmB as Fungizone in rats after a multiple dose regimen, validating the aggregation state hypothesis of AmB .