ReviewsAmphotericin B Formulations and Drug Targeting
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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