Amphotericin B
Clinical data | |
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Trade names | Fungizone, Mysteclin-F, AmBisome and other |
AHFS/Drugs.com | Monograph |
MedlinePlus | a682643 |
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Intravenous infusion | |
ATC code | |
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Pharmacokinetic data | |
Bioavailability | 100% (IV) |
Metabolism | kidney |
Elimination half-life |
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Excretion |
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Identifiers | |
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JSmol) | |
Melting point | 170 °C (338 °F) |
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Amphotericin B is an
Common side effects include a reaction with
Amphotericin B was isolated from
Medical uses
Antifungal
One of the main uses of amphotericin B is treating a wide range of systemic
Antiprotozoal
Amphotericin B is used for life-threatening
Spectrum of susceptibility
The following table shows the amphotericin B susceptibility for a selection of medically important fungi.
Species | Amphotericin B
MIC breakpoint (mg/L) |
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Aspergillus fumigatus | 1[16] |
Aspergillus terreus | Resistant[16][17] |
Candida albicans | 1[16] |
Candida glabrata
|
1[16] |
Candida krusei
|
1[16] |
Candida lusitaniae
|
Intrinsically resistant[17] |
Cryptococcus neoformans | 2[18] |
Fusarium oxysporum | 2[18] |
Available formulations
Intravenous
Amphotericin B alone is insoluble in normal saline at a pH of 7. Therefore, several formulations have been devised to improve its intravenous bioavailability.[19] Lipid-based formulations of amphotericin B are no more effective than conventional formulations, although there is some evidence that lipid-based formulations may be better tolerated by patients and may have fewer adverse effects.[20]
Deoxycholate
The original formulation uses sodium deoxycholate to improve solubility.[17] Amphotericin B deoxycholate (ABD) is administered intravenously.[21] As the original formulation of amphotericin, it is often referred to as "conventional" amphotericin.[22]
Liposomal
In order to improve the tolerability of amphotericin and reduce toxicity, several lipid formulations have been developed.[17] Liposomal formulations have been found to have less renal toxicity than deoxycholate,[23][24] and fewer infusion-related reactions.[17] They are more expensive than amphotericin B deoxycholate.[25]
AmBisome (liposomal amphotericin B; LAMB) is a liposomal formulation of amphotericin B for injection and consists of a mixture of phosphatidylcholine, cholesterol and distearoyl phosphatidylglycerol that in aqueous media spontaneously arrange into unilamellar vesicles that contain amphotericin B.[17][26] It was developed by NeXstar Pharmaceuticals (acquired by Gilead Sciences in 1999). It was approved by the FDA in 1997.[27] It is marketed by Gilead in Europe and licensed to Astellas Pharma (formerly Fujisawa Pharmaceuticals) for marketing in the US, and Sumitomo Pharmaceuticals in Japan.[citation needed]
Lipid complex formulations
A number of lipid complex preparations are also available. Abelcet was approved by the FDA in 1995.[28] It consists of amphotericin B and two lipids in a 1:1 ratio that form large ribbon-like structures.[17] Amphotec is a complex of amphotericin and sodium cholesteryl sulfate in a 1:1 ratio. Two molecules of each form a tetramer that aggregate into spiral arms on a disk-like complex.[26] It was approved by the FDA in 1996.[28]
By mouth
An oral preparation exists but is not widely available.
However, recently novel nanoparticulate drug delivery systems such as AmbiOnp,[31] nanosuspensions, lipid-based drug delivery systems including cochleates, self-emulsifying drug delivery systems,[32] solid lipid nanoparticles[31] and polymeric nanoparticles[33]—such as amphotericin B in pegylated polylactide coglycolide copolymer nanoparticles[34]—have demonstrated potential for oral formulation of amphotericin B.[35] The oral lipid nanocrystal amphotericin by Matinas Biopharma is furthest along having completed a successful phase 2 clinical trial in cryptococcal meningitis.[36]
Side effects
Amphotericin B is well known for its severe and potentially lethal side effects, earning it the nickname "amphoterrible".
Intravenously administered amphotericin B in therapeutic doses has also been associated with multiple organ damage. Kidney damage is a frequently reported side effect, and can be severe and/or irreversible. Less kidney toxicity has been reported with liposomal formulations (such as AmBisome) and it has become preferred in patients with preexisting renal injury.[45][46] The integrity of the liposome is disrupted when it binds to the fungal cell wall, but is not affected by the mammalian cell membrane,[47] so the association with liposomes decreases the exposure of the kidneys to amphotericin B, which explains its less nephrotoxic effects.[48]
In addition, electrolyte imbalances such as
Interactions
Drug-drug interactions may occur when amphorectin B is coadministered with the following agents:[50]
- Flucytosine: Toxicity of flucytosine is increased and allows a lower dose of amphotericin B. Amphotericin B may also facilitate entry of flucystosine into the fungal cell by interfering with the permeability of the fungal cell membrane.
- Diuretics or cisplatin: Increased renal toxicity and increased risk of hypokalemia
- Corticosteroids: Increased risk of hypokalemia
- Imidazole Antifungals: Amphorectin B may antagonize the activity of ketoconazole and miconazole. The clinical significance of this interaction is unknown.
- Neuromuscular-blocking agents: Amphorectin B-induced hypokalemia may potentiate the effects of certain paralytic agents.
- tenofovir, adefovir: Risk of hematological and renal side effects of amphotericin B are increased
- Zidovudine: Increased risk of renal and hematological toxicity .
- Other nephrotoxic drugs (such as aminoglycosides): Increased risk of serious renal damage
- Cytostatic drugs: Increased risk of kidney damage, hypotension, and bronchospasms
- Transfusion of leukocytes: Risk of pulmonal (lung) damage occurs, space the intervals between the application of amphotericin B and the transfusion, and monitor pulmonary function
Mechanism of action
Amphotericin B binds with
Two amphotericins, amphotericin A and amphotericin B, are known, but only B is used clinically, because it is significantly more active in vivo. Amphotericin A is almost identical to amphotericin B (having a C=C double bond between the 27th and 28th carbons), but has little antifungal activity.[19]
Mechanism of toxicity
Mammalian and fungal membranes both contain sterols, a primary membrane target for amphotericin B. Because mammalian and fungal membranes are similar in structure and composition, this is one mechanism by which amphotericin B causes cellular toxicity. Amphotericin B molecules can form pores in the host membrane as well as the fungal membrane. This impairment in membrane barrier function can have lethal effects.[54][55][56] Ergosterol, the fungal sterol, is more sensitive to amphotericin B than cholesterol, the common mammalian sterol. Reactivity with the membrane is also sterol concentration dependent.[57] Bacteria are not affected as their cell membranes do not usually contain sterols.[citation needed]
Amphotericin B administration is limited by infusion-related toxicity. This is thought to result from innate immune production of proinflammatory cytokines.[55][58]
Biosynthesis
The natural route to synthesis includes polyketide synthase components.[59] The carbon chains of amphotericin B are assembled from sixteen 'C2' acetate and three 'C3'propionate units by polyketide syntheses (PKSs).[60] Polyketide biosynthesis begins with the decarboxylative condensation of a dicarboxylic acid extender unit with a starter acyl unit to form a β-ketoacyl intermediate. The growing chain is constructed by a series of Claisen reactions. Within each module, the extender units are loaded onto the current ACP domain by acetyl transferase (AT). The ACP-bound elongation group reacts in a Claisen condensation with the KS-bound polyketide chain. Ketoreductase (KR), dehydratase (DH) and enoyl reductase (ER) enzymes may also be present to form alcohol, double bonds or single bonds.[61] After cyclisation, the macrolactone core undergoes further modification by hydroxylation, methylation and glycosylation. The order of these three post-cyclization processes is unknown.[61]
History
It was originally extracted from
Its complete stereo structure was determined in 1970 by an X-ray structure of the N-iodoacetyl derivative.[60] The first synthesis of the compound's naturally occurring enantiomeric form was achieved in 1987 by K. C. Nicolaou.[63]
Formulations
It is a subgroup of the macrolide antibiotics, and exhibits similar structural elements.[64] Currently, the drug is available in many forms. Either "conventionally" complexed with sodium deoxycholate (ABD), as a cholesteryl sulfate complex (ABCD), as a lipid complex (ABLC), and as a liposomal formulation (LAMB). The latter formulations have been developed to improve tolerability and decrease toxicity, but may show considerably different pharmacokinetic characteristics compared to conventional amphotericin B.[17]
Names
Amphotericin's name originates from the chemical's amphoteric properties.[65]
It is commercially known as Fungilin, Fungizone, Abelcet, AmBisome, Fungisome, Amphocil, Amphotec, and Halizon.[66]
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