Reviews
Amphotericin B Formulations and Drug Targeting

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Abstract

Amphotericin B is a low-soluble polyene antibiotic which is able to self-aggregate. The aggregation state can modify its activity and pharmacokinetical characteristics. In spite of its high toxicity it is still widely employed for the treatment of systemic fungal infections and parasitic disease and different formulations are marketed. Some of these formulations, such as liposomal formulations, can be considered as classical examples of drug targeting. The pharmacokinetics, toxicity and activity are clearly dependent on the type of amphotericin B formulation. New drug delivery systems such as liposomes, nanospheres and microspheres can result in higher concentrations of AMB in the liver and spleen, but lower concentrations in kidney and lungs, so decreasing its toxicity. Moreover, the administration of these drug delivery systems can enhance the drug accessibility to organs and tissues (e.g., bone marrow) otherwise inaccessible to the free drug. During the last few years, new AMB formulations (AmBisome®, Abelcet®, and Amphotec®) with an improved efficacy/toxicity ratio have been marketed. This review compares the different formulations of amphotericin B in terms of pharmacokinetics, toxicity and activity and discusses the possible drug targeting effect of some of these new formulations.

Section snippets

INTRODUCTION

Amphotericin B (AmB) is a polyene antibiotic, which was first isolated in 1955 from Streptomyces nodosus collected from Venezuela.1 AmB is a broad antimycotic agent and a highly antiparasitic one. It is the drug of choice against life-threatening systemic infections with fungi such as Candida albicans or Aspergillus fumigatus. Since invasive fungal infections are a major cause of morbidity and mortality in immunodeficient individuals (such as AIDS patients) and in transplant recipients or tumor

PHYSICAL AND CHEMICAL CHARACTERISTICS

AmB is a yellow/orange-colored natural product that is extracted from cultures of S. Nodosus on a large industrial scale.2 AmB has two characteristically physicochemical properties: amphipilic behavior due to the apolar and polar sides of the lactone ring and amphoteric behavior due to the presence of ionizable carboxyl and amine groups (see Fig. 1). As a consequence of its amphiphilic and zwitterionic nature and the asymmetrical distribution of hydrophobic and hydrophilic groups, AmB is poorly

DRUG FORMULATIONS

The most important drawback to the formulation of AmB is its scarcely solubility in water. In order to obtain drug formulations suitable for intravenous administration two types of AmB formulations have been marketed. Firstly, a mixture of AmB with deoxycholate registered as Fungizone® was developed and it is still the reference conventional formulation. Unfortunately, this formulation is highly nephrotoxic. Reduction of the AmB nephrotoxicity is the most important objective of new lipid AmB

PHARMACOKINETICS

Due to its low solubility AmB gastrointestinal uptake of oral AmB is minimal.4,5 Oral bioavailability improvement is a topic of research and some formulations previously commented such as cochleates91 and nanosuspensions85 have shown interesting results. Recently, an interaction between miltefosine and AmB has been reported to be useful to increase the proportion of AmB in its monomeric form.92 This combination of miltefosine-AmB enhances the gastrointestinal membrane permeability of AmB in

CLINICAL ASSESSMENT

The lipid AmB formulations are among the most expensive anti-infective agents based on a daily dose.55Table 3 shows daily costs with different AmB formulations. The daily cost for an average adult range from around USD 300 to 1300 depending on the formulation and institution.127 This contrasts with Fungizone® which costs approximately USD 5–17 per day.55,127 Lewis127 has pointed out that all drugs have two costs. In addition to their acquisition costs which are shown in Table 3 there are other

Acknowledgements

This work has been partially funded by a grant from the Complutense University and Madrid Community Administration to the research group 910939.

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