Chemical formula: C₄₇H₇₃NO₁₇ Molecular mass: 924.079 g/mol PubChem compound: 5280965
Amphotericin B is a macrocyclic, polyene antifungal antibiotic produced by Streptomyces nodosus. Amphotericin B is fungistatic or fungicidal depending on the concentration attained in body fluids and the susceptibility of the fungus. The molecule is thought to act by binding to sterols in the fungal cell membrane, with a resulting change in membrane permeability, allowing leakage of a variety of small molecules. Mammalian cell membranes also contain sterols, and it has been suggested that the damage to human cells and fungal cells caused by amphotericin B may share common mechanisms. The lipophilic moiety of amphotericin allows the molecule to be integrated into the lipid bilayer of the liposomes. Liposomes are closed, spherical vesicles formed from a variety of amphiphilic substances such as phospholipids. Phospholipids arrange themselves into membrane bilayers when exposed to aqueous solutions.
The pharmacokinetic profile of liposomal amphotericin B (L-AmB), based upon total plasma concentrations of amphotericin B, was determined in cancer patients with febrile neutropenia and bone marrow transplant patients who received 1 hour infusions of 1.0 to 7.5mg/kg/day L-AmB for 3 to 20 days. L-AmB has a significantly different pharmacokinetic profile from that reported in the literature for conventional presentations of amphotericin B, with higher amphotericin B plasma concentrations (Cmax) and increased exposure (AUC0-24) compared to conventional amphotericin B. After the first dose and last dose, the pharmacokinetic parameters of amphotericin B (mean ± standard deviation) ranged from:
Cmax: 7.3 μg/ml (± 3.8) to 83.7 μg/ml (± 43.0)
T1/2: 6.3 hr (± 2.0) to 10.7 hr (± 6.4)
AUC0-24: 27 μg.hr/ml (±14) to 555 μg.hr/ml (± 311)
Clearance (CI): 11 ml/hr/kg (± 6) to 51 ml/hr/kg (± 44)
Volume of distribution (Vss): 0.10 L/kg (± 0.07) to 0.44 L/kg (± 0.27)
Minimum and maximum pharmacokinetic values do not necessarily relate to the lowest and highest doses, respectively. Following administration of liposomal amphotericin B (L-AmB) steady state was reached quickly (generally within 4 days of dosing).
Amphotericin B pharmacokinetics following the first dose of L-AmB appear non-linear such that amphotericin B concentrations are greater than proportional with increasing dose. This non-proportional dose response is believed to be due to saturation of reticuloendothelial L-AmB clearance. There was no significant drug accumulation in the plasma following repeated administration of 1 to 7.5mg/kg/day.
Volume of distribution on day 1 and at steady state suggests that there is extensive tissue distribution of amphotericin B.
After repeated administration of L-AmB, the terminal elimination half-life (t½β) of amphotericin B was approximately 7 hours. The excretion of L-AmB has not been studied. The metabolic pathways of amphotericin B and L-AmB are not known. Due to the size of the liposomes, there is no glomerular filtration and renal elimination of L-AmB, thus avoiding interaction of amphotericin B with the cells of the distal tubuli and reducing the potential for nephrotoxicity seen with conventional amphotericin B presentations.
Renal Impairment:
The effect of renal impairment on the pharmacokinetics of L-AmB has not been formally studied. Data suggest that no dose adjustment is required in patients undergoing haemodialysis or filtration procedures, however, L-AmB administration should be avoided during the procedure.
Mechanism of resistance:
Intrinsic resistance, though rare, may be primarily due to decrease in ergosterol or a change in the target lipid, leading to reduced binding of amphotericin B to the cell membrane.
Breakpoints:
EUCAST breakpoints for L-AmB have not yet been established, however, susceptibility to L-AmB may differ to that of amphotericin B deoxycholate.
Amphotericin B, the antifungal component of L-AmB, is active in vitro against many species of fungi, most strains of Histoplasma capsulatum, Coccidioides immitis, Candida spp, Blastomyces dermatidis, Rhodotorula, Cryptococcus neoformans, Sporothrix schenkii and Aspergillus fumigatus, Penicillium marneffi, and members of the mucormycetes group of moulds including Mucor mucedo, Rhizomucor and Rhizopus oryzae.
The majority of clinically important fungal species seem to be susceptible to amphotericin B, although intrinsic resistance has rarely been reported, for example, for some strains of S. schenckii, C. glabrata, C.krusei, C. tropicalis, C. lusitaniae, C. parapsilosis and Aspergillus terreus.
L-AmB has been shown to be effective in animal models of visceral leishmaniasis (caused by Leishmania infantum and Leishmania donovani).
In subchronic toxicity studies in dogs (1 month), rabbits (1 month) and rats (3 months) at doses equal to or, in some species, less than the clinical therapeutic doses of 1 to 3 mg/kg/day, the target organs for amphotericin B toxicity were the liver and kidneys with thrombocytopenia also observed. All are known targets for amphotericin B toxicity.
Amphotericin B was found to be non-mutagenic in bacterial and mammalian systems.
Carcinogenicity studies have not been conducted with amphotericin B.
No adverse effects on male or female reproductive function were noted in rats.
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