Dórea E L, Yu L, De Castro I, Campos S B, Ori M, Vaccari E M, Lacaz C da S, Seguro A C
Laboratório de Pesquisa Básica da Disciplina de Nefrologia da Faculdade de Medicina da Universidade de São Paulo, Brazil.
J Am Soc Nephrol. 1997 Sep;8(9):1415-22. doi: 10.1681/ASN.V891415.
Nephrotoxicity is the major adverse effect of conventional amphotericin B (AMB/D), often limiting administration of full dosage. The new liposomal amphotericin B seems to be less toxic. The new liposomal amphotericin B seems to be less toxic. In this study, it is proposed that solubilizing the standard AMB/D preparation with 10% lipid emulsion will attenuate nephrotoxicity. Rats were injected with either AMB/D (Fungizone), AMB, AMB/D plus lipid emulsion (AMB/D/LE), or sodium deoxycholate (D). Renal function studies were performed on day 5. To assess a direct tubular toxic effect, isolated rat proximal tubule suspensions and inner medullary collecting duct cells in culture were exposed to AMB/D, AMB, AMB/D/LE, liposomal amphotericin B, and D for 60 min in normoxia. Lactate dehydrogenase (LDH) release was assessed as an index of cell injury. Creatinine clearance (ml/min per 100 g) averaged 0.79 +/- 0.04 in control rats, 0.29 +/- 0.09 in AMB rats (P < 0.001 versus control), 0.38 +/- 0.04 in AMB/D rats, 0.46 +/- 0.05 in D rats, and 0.78 +/- 0.03 in AMB/LE rats. Renal blood flow (ml/min per 100 g) was 3.45 +/- 0.31 in control, 1.29 +/- 0.28 in AMB, 1.42 +/- 0.23 in AMB/D, 3.03 +/- 0.39 in D, and 2.71 +/- 0.21 in AMB/D/LE rats. The fractional excretion of potassium (%) was 27.3 +/- 1.18 in control rats, 61.6 +/- 7.00 in AMB/D rats, 58.4 +/- 15.32 in AMB rats, and 37.9 +/- 2.06 in AMB/D/LE rats. LDH release (%) in proximal tubules incubated with AMB/D and D was 43.6 +/- 3.39 and 58.6 +/- 4.20, respectively. Addition of lipid emulsion decreased LDH release: 21.6 +/- 1.22 for AMB/D/LE and 26.4 +/- 3.03 for deoxycholate plus lipid emulsion. AMB did not demonstrate any toxic effect in proximal tubule suspensions. D was not toxic to inner medullary collecting duct cells at 0.16 mg/ml, whereas D at a higher dose and AMB induced a significant LDH release. Addition of lipid emulsion did not affect the antifungal activity as assessed by the Etest method. In conclusion, an alternative way of administering standard AMB with reduced nephrotoxicity is proposed.
肾毒性是传统两性霉素B（AMB/D）的主要不良反应，常常限制其全剂量给药。新型脂质体两性霉素B的毒性似乎较小。在本研究中，有人提出用10%脂质乳剂溶解标准AMB/D制剂会减轻肾毒性。给大鼠注射AMB/D（两性霉素B）、AMB、AMB/D加脂质乳剂（AMB/D/LE）或脱氧胆酸钠（D）。在第5天进行肾功能研究。为评估直接的肾小管毒性作用，将分离的大鼠近端肾小管悬液和培养的髓质集合管细胞在常氧条件下暴露于AMB/D、AMB、AMB/D/LE、脂质体两性霉素B和D中60分钟。评估乳酸脱氢酶（LDH）释放作为细胞损伤的指标。对照大鼠的肌酐清除率（每100克毫升/分钟）平均为0.79±0.04，AMB大鼠为0.29±0.09（与对照相比P<0.001），AMB/D大鼠为0.38±0.04，D大鼠为0.46±0.05，AMB/LE大鼠为0.78±0.03。肾血流量（每100克毫升/分钟）在对照中为3.45±0.31，AMB中为1.29±0.28，AMB/D中为1.42±0.23，D中为3.03±0.39，AMB/D/LE大鼠中为2.71±0.21。钾的分数排泄率（%）在对照大鼠中为27.3±1.18，AMB/D大鼠中为61.6±7.00，AMB大鼠中为58.4±15.32，AMB/D/LE大鼠中为37.9±2.06。与AMB/D和D孵育的近端肾小管中LDH释放率（%）分别为43.6±3.39和58.6±4.20。添加脂质乳剂降低了LDH释放：AMB/D/LE为21.6±1.22，脱氧胆酸钠加脂质乳剂为26.4±3.03。AMB在近端肾小管悬液中未显示任何毒性作用。D在0.16毫克/毫升时对髓质集合管细胞无毒，而较高剂量的D和AMB诱导了显著的LDH释放。添加脂质乳剂不影响用Etest法评估的抗真菌活性。总之，提出了一种给药标准AMB且降低肾毒性的替代方法。
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