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

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

Volume: 4 Issue: 1

Author(s): Jeong Yeon Kang, Jieming Gao, Dae Hwan Shin, Celeste Alvarez, Weixiong Zhong and Glen S. Kwon

Affiliation:

Keywords: Aggregation state, amphotericin B, antifungal, polymeric micelle, nephrotoxicity, pharmacokinetics, systemic fungal disease.

Abstract: 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)-block-poly(N-hexyl stearate Laspartamide) (PEG-b-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_d) 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 causes less renal toxicity than AmB as Fungizone^® in rats after a multiple dose regimen, validating the aggregation state hypothesis of AmB in vivo.

Cite this article as:

Yeon Kang Jeong, Gao Jieming, Hwan Shin Dae, Alvarez Celeste, Zhong Weixiong and S. Kwon Glen, Pharmacokinetics and Renal Toxicity of Monomeric Amphotericin B in Rats after a Multiple Dose Regimen, Pharmaceutical Nanotechnology 2016; 4 (1) . https://dx.doi.org/10.2174/2211738504666160301233754