title: Pharmacokinetics and Renal Toxicity of Monomeric Amphotericin B in Rats after a Multiple Dose Regimen.
abstract: 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.
  
  
  
  The aim of this study was to characterize the pharmacokinetic (PK) and renal toxicity of monomeric AmB in rats following a multiple dose regimen.
  
  
  
  AmB existed primarily in a monomeric state in poly(ethylene glycol)-block-poly(N-hexyl stearate L-aspartamide) (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.
  
  
  
  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 (Vd) 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.
  
  
  
  In summary, mAmB has less renal toxicity than AmB as Fungizone®in rats after a multiple dose regimen, validating the aggregation state hypothesis of AmBin vivo.
authors: Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, Madison, WI 53705.
authors: Jeong Yeon
authors: JY
authors: Kang
authors: Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, Madison, WI 53705.
authors: Jieming
authors: J
authors: Gao
authors: Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, Madison, WI 53705.
authors: Dae Hwan
authors: DH
authors: Shin
authors: Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, Madison, WI 53705.
authors: Celeste
authors: C
authors: Alvarez
authors: Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI 53792.
authors: Weixiong
authors: W
authors: Zhong
authors: Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, Madison, WI 53705.
authors: Glen S
authors: GS
authors: Kwon
mesh_terms: D000118:Acetylglucosaminidase / Q000378:metabolism; D000666:Amphotericin B / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004334:Drug Administration Schedule; D004337:Drug Carriers / Q000737:chemistry*; D007668:Kidney / Q000187:drug effects*; D008297:Male; D008823:Micelles; D011091:Polyesters / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
chemical_list: D000935:Antifungal Agents; D004337:Drug Carriers; D008823:Micelles; D011091:Polyesters; C416209:poly(ethylene oxide)-block-poly(N-hexyl stearate) aspartamide; D011092:Polyethylene Glycols; D000666:Amphotericin B; D000118:Acetylglucosaminidase
keywords: aggregation state; amphotericin B; antifungal; nephrotoxicity; pharmacokinetics; polymeric micelle; systemic fungal disease