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

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 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. 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 (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. 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 in vivo.

Ursolic Acid Potentializes Conventional Therapy in Experimental Leishmaniasis

“…By adding UA to the therapy, significant reduction in the splenic and hepatic parasitism was observed, suggesting that this triterpene potentialized AmB activity, mainly the doses of 0.2 and 1.0 mg/kg. In the monotherapy regimen, performed with AmB, reduction in the parasitism in the both spleen and liver was detected only in the highest dose studied (5.0 mg/kg); this means that AmB becomes active in vivo when animals receive a total dose of 18.75 mg, that according to previous works, this amount of drug, as well as lower ones, induced severe morphological and biochemical changes in the kidney of the experimental animals [ 21 , 31 ]. In contrast, non-therapeutic doses of AmB became therapeutic when combined with the triterpene UA, and it can be considered as an advantage, since combination carried out with low doses of AmB and UA eliminated an elevated number of viable parasites and also may induce less side-effects to the host.…”

Promising Drug Delivery Approaches to Treat Microbial Infections in the Vagina: A Recent Update

“…In this context, Kim et al formulated a thermosensitive in situ vaginal gel using Pluronic-based triblock copolymer derivative (MBCP-2) loaded with AmB which could selectively degrade under acidic vaginal conditions [146]. Similar to the previous study, the incorporation of AmB as an inclusion complex with hydroxypropylγ-cyclodextrin (HPγCD) increased its aqueous solubility [143,145]. It was demonstrated that the AmB-HPγCD complex-loaded MBCP-2 gel underwent a sol-to-gel transition at body temperature (37 • C) and exhibited a pH-dependent degradation.…”

“…On the other hand, the clinical use of AmB is limited because of its toxic side effects and low aqueous solubility [ 144 , 145 ]. In this context, Kim et al formulated a thermosensitive in situ vaginal gel using Pluronic-based triblock copolymer derivative (MBCP-2) loaded with AmB which could selectively degrade under acidic vaginal conditions [ 146 ].…”

Lipid Systems for the Delivery of Amphotericin B in Antifungal Therapy

“…The antibiotic targets the cellular membrane, showing higher affinity for ergosterol-containing membranes typical of fungal cells than for cholesterol-containing membranes of mammalian host cells [44,53,54]. AmB oligomers are particularly toxic to eukaryotic cells leading to high antifungal activity but also severe toxic side effects [43][44][45][46]48,49,51,55] while polyaggregated and monomeric forms of the drug retain antifungal activity and show reduced toxicity towards host cells [43,49,51]. This suggests that better selectivity for fungal cells leading to improved therapeutic index may be achieved by carefully controlling the aggregation state of the drug [25,43,45,46], which can be easily determined from AmB ultraviolet (UV) absorption or fluorescence spectra that are sensitive to different aggregation states [46,56].…”

“…Disruption of ergosterol biosynthesis is responsible for resistance to Due to its amphipathic nature, AmB is able to self-associate in aqueous solution forming water soluble dimers and oligomers that can further associate to form insoluble polyaggregates, which act as a monomer reservoir [25,[43][44][45][46]. The nature and proportion of each species in both aqueous and lipid phases is dependent on total drug concentration, temperature, type of formulation, and membrane composition, being correlated with AmB efficacy and toxicity [43][44][45][46][47][48][49][50][51]. Drug morphology (crystalline or amorphous state) and formulation techniques also influence the rate of dissolution and solubility of AmB [52].…”