In-vitro and in-vivo studies of the decrease of amphotericin B toxicity upon association with a triglyceride-rich emulsion

Souza, Liliete Canes; Maranhão, Raul C.; Schreier, Shirley; Čampa, Ana

doi:10.1093/jac/32.1.123

Cited by 43 publications

(32 citation statements)

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“…administration of AMB has been limited by its dose-dependent kidney toxicity that has not been predictable by monitoring plasma and/or serum drug concentrations (6,13,22). A number of studies have reported that AMB solubilized in methanol is poorly absorbed from the GI tract (3,10,17,19), and therefore it is not commonly administered orally but i.v., which can result in the aforementioned renal toxicity. However, to date, few studies investigating the development and evaluation of an oral AMB formulation have been reported.…”

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

Risovic¹,

Boyd

Choo³

et al. 2003

Antimicrob Agents Chemother

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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...

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

Risovic¹,

Boyd

Choo³

et al. 2003

Antimicrob Agents Chemother

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“…Muitos trabalhos foram direcionados ao desenvolvimento de preparações lipídicas como veículo para fármacos, como lipossomas (Lopez-Berestein et al, 1983;Hospenthal, Rogers, Mills, 1988;Hospenthal, Gretzinger, Rogers, 1989;Chopra et al, 1991), complexos lipídicos (Janoff et al, 1988;Balakrishnan, Easwaran, 1993) e emulsões (Kirsh et al, 1988;Illum et al, 1989;Miyazaki et al, 1990;Chavanet et al, 1992a;Souza et al, 1993). Os lipossomas foram inicialmente utilizados para estudar o fluxo de íons através das membranas celulares (Borisova, Erminshkin, Silberstein, 1979;Kasumov et al, 1979;VertutCroquin et al, 1983;Cybulska et al, 1985), mas as principais razões dos estudos posteriores foram a necessidade de reduzir a toxicidade e a possibilidade de utilização dos mecanismos farmacocinéticos dessas formulações, a fim de melhorar a distribuição de fármacos nos órgãos-alvo (Kan et al, 1991;Walsh et al, 1998;Adedoyin et al, 2000;Bekersky et al, 2002).…”

Section: Formulações Lipídicas De Abunclassified

“…A primeira teoria proposta teve como base a maior afinidade de AB por ergosterol que por colesterol (Bolard, 1986) e foi sustentada pela redução de toxicidade observada em eritrócitos com manutenção dos efeitos tóxicos para células de fungos (Juliano et al, 1986;Midez et al, 1989;Souza, et al, 1993). Assim, quando o antifúngico estivesse associado às formulações lipídicas, sua disponibilidade para células de mamífe-ros seria reduzida, permanecendo tóxica para células de fungos.…”

Section: Mecanismos Propostos Para Redução De Toxicidadeunclassified

“…Estudos pré-clínicos foram realizados empregando-se AB-emulsão com composição lipídica (70% trioleína, 27% fosfatidilcolina e 3% colesterol) e metabolização similar a quilomícrons da linfa (Souza et al, 1993;Souza, Campa, 1999). Neste contexto, AB-emulsão foi desenvolvida e avaliada através de ensaios in vitro demonstrando redução da toxicidade em leucócitos PMN (Marzzullo, Souza, Campa, 1997) e em eritrócitos, bem como a manutenção da eficiência de AB contra Candida albicans (Souza et al, 1993). Estes resultados foram condizentes com estudos in vivo em que ratos e camundongos foram utilizados para avaliação histopatológica e farmacológica, observando-se redução dos efeitos tóxicos de AB (Souza, Saldiva, Campa, 2000).…”

Section: Mecanismos Propostos Para Redução De Toxicidadeunclassified

“…Assim, quando comparada AB-emulsão com a formulação comercial AB-DOC, demonstrou-se redução dos efeitos tóxicos in vitro (incubação com eritrócitos) e in vivo (administração em ratos) quando esta foi veiculada à emulsão (Souza et al, 1993). A redução de toxicidade de AB-emulsão nos rins foi avaliada por Souza, Saldiva e Campa (2000), que observaram menor dano renal para AB-emulsão, se comparada com AB-DOC, diferentemente das demais formulações lipídicas.…”

Section: Mecanismos Propostos Para Redução De Toxicidadeunclassified

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