BEHAVIOR OF AMPHOTERICIN-B LIPID COMPLEX IN PLASMA IN-VITRO AND IN THE CIRCULATION OF RATS

Amphotericin B lipid complex (ABLC) shows reduced toxicity relative to that of amphotericin B deoxycholate (AmB-d) while maintaining antifun gal activity. Rat blood or plasma was spiked with ABLC in vitro. Relea sed amphotericin B was separated from the parent material by centrifug ation. At early times (0 to 15 min) most (similar to 90%) of the ampho tericin B was complexed. The amount of released amphotericin B increas ed gradually in a time- and temperature-dependent fashion. The release d amphotericin B was associated with plasma lipoprotein and nonlipopro tein proteins. The area under the concentration-time curve from 0 to 2 4 h for total amphotericin B in whole blood of rats given a single int ravenous bolus dose of 1 mg of ABLC per kg of body weight was fourfold lower than that in rats given 1 mg of AmB-d per kg. The complexed amp hotericin B was rapidly removed from the circulation and was distribut ed to the tissues in these rats. Other rats were treated intravenously with ABLC (10 mg/kg/day) or AmB-d (0.5 mg/kg/day) daily for 15 days. Blood was collected at 15 and 180 min after administration of the last dose. The total levels of amphotericin B in the blood of the group gi ven ABLC were about three to five times those in the group given AmB-d , and the concentration of released, protein-bound amphotericin B in t he plasma of the group given ABLC was about one to two times that obse rved for the group given AmB-dt, despite the 20-fold difference in dos e. The relative protein distribution of amphotericin B in plasma was s imilar after ABLC or AmB-d administration under these steady-state con ditions in vivo. The rapid uptake of complexed amphotericin B by tissu es and the ver low levels of circulating protein-bound amphotericin B in plasma after the administration of ABLC may explain, in part, the r educed toxicity and enhanced therapeutic index of this preparation.