Aramwit P, Yu B G, Lavasanifar A, Samuel J, Kwon G S
School of Pharmacy, University of Wisconsin at Madison, Madison, Wisconsin 53706-1515, USA.
J Pharm Sci. 2000 Dec;89(12):1589-93. doi: 10.1002/1520-6017(200012)89:12<1589::aid-jps10>3.0.co;2-6.
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 toxicity of AmB, we have investigated the effect of serum albumin, the most abundant plasma protein, on the aggregation state of AmB using absorption spectroscopy. The critical aggregation concentration (CAC) of AmB, which coincides with its concentration at the onset of toxicity (hemolysis), was 1.1 microM, but rose in proportion to the level of serum albumin (1.0 to 4.0% w/v). The CAC of AmB was 8.0 microM at 4.0% w/v serum albumin, which is considerably higher than peak therapeutic levels of AmB in plasma (i.e., 2.0 microM). Serum albumin (4.0% w/v) lowered the degree of aggregation of AmB (size of aggregates) above the CAC and increased its solubility. The results suggest that serum albumin attenuates the toxicity of AmB at a membrane level by affecting its aggregation state. In this way, serum albumin in blood may balance deleterious effects of AmB mediated by serum low-density lipoproteins.
研究表明，两性霉素B（AmB）是治疗系统性真菌病的关键药物，其剂量限制性毒性取决于自身的聚集状态。为了进一步了解血液中影响AmB毒性的各种因素，我们利用吸收光谱法研究了血浆中含量最丰富的蛋白质——血清白蛋白对AmB聚集状态的影响。AmB的临界聚集浓度（CAC）与其毒性发作时（溶血）的浓度一致，为1.1微摩尔，但随血清白蛋白水平（1.0至4.0% w/v）成比例上升。在血清白蛋白浓度为4.0% w/v时，AmB的CAC为8.0微摩尔，远高于血浆中AmB的治疗峰值水平（即2.0微摩尔）。血清白蛋白（4.0% w/v）降低了AmB在临界聚集浓度以上的聚集程度（聚集体大小），并提高了其溶解度。结果表明，血清白蛋白通过影响AmB的聚集状态在膜水平上减轻其毒性。通过这种方式，血液中的血清白蛋白可能平衡血清低密度脂蛋白介导的AmB的有害作用。
