Effects of Lipid-Based Oral Formulations on Plasma and Tissue Amphotericin B Concentrations and Renal Toxicity in Male Rats

Abstract

The purpose of this study was to determine the effects of various lipid and mixed-micelle formulations on the oral absorption and renal toxicity of amphotericin B (AMB) in rats. The maximum concentration of AMB in plasma and the area under the concentration-time curve for 0 to 24 h for AMB were elevated in rats administered triglyceride (TG)-rich AMB formulations in comparison to those in rats given (i) AMB preformulated as a micelle containing sodium deoxycholate with sodium phosphate as a buffer (DOC-AMB), (ii) an AMB-lipid complex suspension, or (iii) AMB solubilized in methanol. Furthermore, our findings suggest that AMB incorporated into TG-based oral formulations has less renal toxicity than DOC-AMB.Despite the development of a number of new antifungal agents (6), amphotericin B (AMB) formulated as a micellar suspension (Fungizone; Bristol-Myers Squibb, Princeton, N.J.) remains one of the most effective agents in the treatment of systemic fungal infections (13). However, its use is often limited by the development of kidney toxicity manifested by renal vasoconstriction with a significant decrease in the glomerular filtration rate and renal plasma flow and by the wasting of renal potassium and magnesium (6,13,22). A number of studies have reported that monomeric AMB that is solubilized in methanol is poorly absorbed from the gastrointestinal (GI) tract (3,10,19), and therefore it is not commonly administered orally but intravenously (i.v.), which can result in the aforementioned renal toxicity.Improved GI absorption of poorly absorbable drugs can be achieved by increasing the dissolution rate of the drug in the presence of bile acids. Within the GI tract, bile salts behave as biological detergents that, when mixed with phospholipids, form thermodynamically stable mixed micelles. Numerous studies have reported enhanced absorption of poorly absorbable drugs when administered as mixed micellar solutions (7,14,23). In addition, when AMB was incorporated into mixed micelles containing bile acids and phospholipids, it resulted in increased intestinal permeability and subsequent GI absorption when a rat intestinal-perfusion methodology was used (3). However, the limitation of that study was that various AMB mixed-micelle formulations were perfused through a cannulated upper intestine of an anesthetized rat. This model does not account for the effect of anesthesia and was not done in a whole-animal model. Furthermore, the toxicological consequences of improving GI absorption, specifically, the dosedependent kidney toxicity of AMB which limits the use of this compound, were not investigated in this study.Thus, the purpose of our study was to determine the effects of various lipid and mixed-micelle formulations on the oral absorption and renal toxicity of AMB in rats. Based on preliminary studies, our working hypothesis was that the incorporation of AMB into mixed micelles composed of mono-and diglycerides and phospholipids would significantly enhance GI tract absorption, resulting in increased concentration in plasm...

A Novel Nanocapsule Delivery System to Overcome Intestinal Degradation and Drug Transport Limited Absorption of P-glycoprotein Substrate Drugs

“…Constantinides and Wasan (10) recently reviewed additional pharmaceutical approaches for enhancing intestinal absorption of P-gp substrate drugs by using excipient inhibitors that exhibit minimal nonspecific pharmacological inhibition activity in the lipid formulations. Until now, only encouraging in vitro and animal study results have been published (5,11) although toxic effects resulting from chronic administration of these excipient inhibitors cannot be excluded. Furthermore, attempts were made to improve the oral absorption of P-gp substrates by incorporating the drugs in the inner oil cores of emulsion formulations which exhibited better absorption profiles (12)(13)(14).…”

Biodegradable Nanoparticles Improve Oral Bioavailability of Amphotericin B and Show Reduced Nephrotoxicity Compared to Intravenous Fungizone®

“…Oral delivery could improve patients' compliance and pharmacokinetics of a drug. A huge number of formulations have been reported to improve the delivery of AMB; however, a few formulations have been investigated for AMB oral delivery, which includes nanosuspension and lipid formulations of AMB viz., Peceol-AMB and chochleates-AMB (10)(11)(12). The nanosuspension was successful in improving the solubility of AMB, which is thought to be primary requirement for an oral formulation; however, such formulations may not offer protection from GIT degradation or prevent P-gp efflux.…”

Assessing the Antifungal Activity of a New Oral Lipid-Based Amphotericin B Formulation Following Administration to Rats Infected withAspergillus Fumigatus

“…We further observed that AmpB incorporated into Peceol was less renal toxic than either intravenous or orally administered DOC-AmpB by decreasing the concentration of AmpB recovered in the kidney and increasing the concentration of AmpB recovered in the liver and spleen (Risovic et al, 2003). However, to date, AmpB's antifungal activity following the administration of this new oral formulation has yet to be assessed.…”

“…Based on previous studies (Risovic et al, 2003) our working hypothesis was that incorporation of AmpB into Peceol would significantly enhance GI tract absorption resulting in increased plasma concentration and decreased organ colony forming units of Aspergillus fumigatus compared to non-treated controls.…”

“…Recently, our laboratory has determined that plasma AmpB levels were significantly elevated in rats following the oral administration of AmpB incorporated into Peceol (a lipid-based excipient composed of comprised primarily of a mixture of mono-and diglycerides of oleic acid, which closely resembles the endproducts of intestinal lipid digestion (Hauss et al, 1998) compared to DOC-AmpB or AmpB solubilized in methanol (Risovic et al, 2003). We further observed that AmpB incorporated into Peceol was less renal toxic than either intravenous or orally administered DOC-AmpB by decreasing the concentration of AmpB recovered in the kidney and increasing the concentration of AmpB recovered in the liver and spleen (Risovic et al, 2003).…”