bioavailability and toxicity between the various lipid formulations of amphotericinb


Amphotericin B (AmB) a lipophilic drug formulated with deoxycholate and a micellar dispersion. Treats fungal infections against a broad range of pathogenic fungi Montoro-Ronsano.B.J et al. (2001). It has severe side effects e.g chills, fever, nausea and headache Larabi.M et al. (2004).

Despite the broad spectrum activity of AmB, the efficacy of this polyene drug is limited by poor bioavailability and toxicity Heinemann.V et al (1997). Efforts to improve the improve the amphipathic nature, bioavailability and toxicity have been ongoing. Lipid formulations of AmB developed are: Abelcet, Amphocil and Ambisome MacDonald.J et al. (1997).

Abelcet (ABLC)

A lipid non- haemolytic complex, containing AmB and reduced toxicity in animals. Has a ribbon-like structure and retains the activity of AmB against pathogens. In a review by Bekersky. I et al it states that Abelcet has rapid clearance time from the plasma into tissues and organs Bekersky. I et al. (1999). Abelcet is taken up by phagocytic cells of the mononuclear phagocyte system (MPS) and concentrates in the liver, spleen and lungs. Has similar side effects e.g chills and fever as compared to standard AmB Tiphine.M et al. (1997.

Amphocil (Amphotec, ABCD)

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A a stable unique disc-shaped particles of uniform size which has mixture of AmB and cholesterol sulphate. It reduces hemolysis, hacacute toxicity and lipoprotein binding of AmB. Has a rapid clearance time and an increased therapeutic index in animals. Although it has minor side effects than AmB but reduced renal toxicity Bekersky. I et al. (1999). ABCD is taken up by the reticuloendothelial system, resulting in low plasma concentrations and a high volume of distribution (Vd) Tiphine.M et al. (1997).

AmBisome (AmBi)

A liposomal formulation with saturated phospholipids with cholesterol to stabilise the liposomal membrane. A charged phospholipid (phosphatidylglycerol) to stabilise the AmB liposomes. Known to have a high therapeutic index and it retains its activity of AmB against wide range of fungi. Ambisome remains in the plasma for a longer period therefore increasing plasma concentration and accumulates in the tissues of liver and spleen Bekersky. I et al. (1999).

The similarities between them is that all formulations use lipids to stabilise AmB. They have a broad-spectrum antifungal activity, less toxic, increased therapeutic index, rapid clearance time, oral bioavalibility of <5% and although many of them are less active for the treatment of fungal infections, by giving high doses better anti-fungal action is achieved Torrado.J.J et al. (2008). They reduce uptake and toxicity in the kidneys and the tissues but have similar side effects but no unique side effects. Bekersky. I et al. (1999).

The formulations do differ in the plasma pharmacokinetics. ABCD and ABLC, have a rapid clearance time and lower plasma levels than standard AmB. AmBi, has a slower clearance time resulting in much higher levels of total AmB in plasma Bekersky. I et al. (1999). Volume of distribution (Vd) is smaller for AmBi and ABLC has high Vd (table 1) Tiphine.M et al. (1997).

Table 1- amphotericin B and its lipid formulations in humans Tiphine.M et al. (1997).

A report by Montoro-Ronsano.B. J et al showed similar results with post-hoc analysis. The reduced toxicity of the formulations that present lower AUC is due to the reduced plasma levels of AmB and a high Vd indicates the access of AmB to sites of fungal infections. (Montoro-Ronsano.B.J et al. (2001).

In a recent study all the formulations tested in vivo at high doses AmBi was the most effective at lower single doses and was least toxic to mice. AmBi acts as a reservoir of drug, which increases the circulation time of AmB and permits prolonged tissue exposure Yardley.V and Croft.L.C. (1999). ABLC and ABCD are taken up reticulo-endothelial system tissues, with peak <5mg/L plasma levels when given '1-10 mg⁄ kg' doses. However, AmBi at similar doses produceds peak plasma levels '25-200 times greater' than ABLC and ABCD Adler-Moore.P.J and Proffitt.T.R. (2008). ABLC and AmBi bind selectively to high density lipoproteins (HDL) and ABCD poorly. As ABCD has less LDL bound AmB and low peak serum levels, it causes reduced nephrotoxicity (Tiphine.M et al. (1997).

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The acute side effects are more in the ABLC and ABCD, indicating rapid clearance time might be contributing to these side-effects. All the 3 preparations have high AmB concentrations and the kidney concentrations are similar as compared to standard AmB. The ability of these formulations to reduce renal toxicity is due to the reduced renal drug exposure. Bekersky. I et al. (1999). In a study done by Mouton.W.J et al on a 'non-neutropenic model of invasive aspergillosis', AmBi and ABLC were more effective than AmB. Mouton.W.J et al. (2009). In a double-blind study between AmBi and ABLC, AmBi had a lower toxicity, '14.8% vs. 42.3%' indicating reduced nephrotoxicity as compared to Fungisome (AmB/detergent solution). It is also found that the efficacy in treatment of fungal infections of these drugs in rank for in-vitro comparative anti-fungal activity is: 'Fungisome>Abelcet>Amphotec>AmBisome', with Ambiome being most effective Torrado.J.J et al. (2008).

An in-vitro toxicity study has been performed in which red blood cell (RBC) lysed with each of the formulations. It was found that the formulations were less haemolytic than AmB. The in-vivo toxicity was also studied in mice and the results showed that a single intravenous dose of AmB, ABCD, ABLC and AmBi that caused death of 50% of mice was '2-3 mg⁄ kg for AmB, 36- 38 mg⁄ kg for ABCD, 40 mg⁄ kg for ABLC and 175 mg⁄ kg for AmBi'. Indicating multiple-dose toxicity studies reflect the toxicities of the AmB lipid formulations. AmBi is less toxic than either ABCD and ABLC Adler-Moore.P.J and Proffitt.T.R. (2008).

A disadvantage is that, due to the lipid formulation colloidal nature, they are removed from circulations by cells of the mononuclear phagocyte system, causing hepatic disorders. Some authors suggest to combine AmB with the lipid emulsions e.g Intralipid but further investigations need to be done Lemke. A et al (2005).

In conclusion with proven efficacy lipid-based AmB formulations have improved safety and clinical performance of a toxic but highly effective drug. By reducing the chronic nephrotoxicity, rapid clearance time and high therapeutic index it allows researchers to adopt new, more effective strategies for treating fungal infections as well as offering a safer high dose administration for patients. AmBi appears to be the safest of the three formulation, with good bioavailability and less side effects it outweighs its high costs.