NEPHROTOXICITY OF AMPHOTERICIN-B IS ATTENUATED BY SOLUBILIZING WITH LIPID EMULSION

Nephrotoxicity is the major adverse effect of conventional amphoterici n B (AMB/D), often limiting administration of full dosage. The new lip osomal amphotericin B seems to be less toxic. In this study, it is pro posed 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 sodi um deoxycholate (D). Renal function studies were performed on day 5. T o assess a direct tubular toxic effect, isolated rat proximal tubule s uspensions and inner medullary collecting duct cells in culture were e xposed 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) avera ged 0.79 +/- 0.04 in control rats, 0.29 +/- 0.09 in AMB rats (P < 0.00 1 versus control), 0.38 +/- 0.04 in AMB/D rats, 0.46 +/- 0.05 in D rat s, 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 i n AMB/D, 3.03 +/- 0.39 in D, and 2.71 +/- 0.21 in AMB/D/LE rats. The f ractional 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. A ddition 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, whe reas D at a higher dose and AMB induced a significant LDH release. Add ition of lipid emulsion did not affect the antifungal activity as asse ssed by the Etest method. In conclusion, an alternative way of adminis tering standard AMB with reduced nephrotoxicity is proposed.