The effect of serum albumin on the aggregation state and toxicity of amphotericin B

Studies have shown that the dose-limiting toxicity of amphotericin B (AmB), a key drug for systemic mycoses, depends on its self-aggregation state. In a step toward understanding the various factors in blood mediating the tox icity of AmB, we have investigated the effect of serum albumin, the most ab undant plasma protein, on the aggregation state of AmB using absorption spe ctroscopy. The critical aggregation concentration (CAC) of AmB, which coinc ides with its concentration at the onset of toxicity (hemolysis), was 1.1 m uM, but rose in proportion to the level of serum albumin (1.0 to 4.0% w/v). The CAC of AmB was 8.0 muM at 4.0% w/v serum albumin, which is considerabl y higher than peak therapeutic levels of AmB in plasma (i.e., 2.0 muM). Ser um albumin (4.0% w/v) lowered the degree of aggregation of AmB (size of agg regates) above the CAC and increased its solubility. The results suggest th at serum albumin attenuates the toxicity of AmB at a membrane level by affe cting its aggregation state. In this way, serum albumin in blood may balanc e deleterious effects of AmB mediated by serum low-density lipoproteins. (C ) 2000 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 89: 15;89-1593, 2000.