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 antifungal activity. Rat blood or plasma was spiked with ABLC in vitro. Released amphotericin B was separated from the parent material by centrifugation. At early times (0 to 15 min) most (approximately 90%) of the amphotericin B was complexed. The amount of released amphotericin B increased gradually in a time- and temperature-dependent fashion. The released amphotericin B was associated with plasma lipoprotein and nonlipoprotein proteins. The area under the concentration-time curve from 0 to 24 h for total amphotericin B in whole blood of rats given a single intravenous 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 amphotericin B was rapidly removed from the circulation and was distributed 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 given ABLC were about three to five times those in the group given AmB-d, and the concentration of released, protein-bound amphotericin B in the plasma of the group given ABLC was about one to two times that observed for the group given AmB-d, despite the 20-fold difference in dose. The relative protein distribution of amphotericin B in plasma was similar after ABLC or AmB-d administration under these steady-state conditions in vivo. The rapid uptake of complexed amphotericin B by tissues and the very low levels of circulating protein-bound amphotericin B in plasma after the administration of ABLC may explain, in part, the reduced toxicity and enhanced therapeutic index of this preparation.
Bhamra
R
R
The Liposome Company, Inc., Princeton, New Jersey 08540, USA.
Sa'ad
A
A
Bolcsak
L E
LE
Janoff
A S
AS
Swenson
C E
CE
D000666:Amphotericin B / Q000008:administration & dosage / Q000097:blood* / Q000378:metabolism / Q000493:pharmacokinetics*; D000818:Animals; D000935:Antifungal Agents / Q000097:blood* / Q000378:metabolism / Q000493:pharmacokinetics*; D002784:Cholesterol / Q000097:blood; D002851:Chromatography, High Pressure Liquid; D003840:Deoxycholic Acid / Q000008:administration & dosage / Q000378:metabolism; D004338:Drug Combinations; D008297:Male; D010713:Phosphatidylcholines / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics*; D010715:Phosphatidylglycerols / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000935:Antifungal Agents; D004338:Drug Combinations; D010713:Phosphatidylcholines; D010715:Phosphatidylglycerols; C068538:liposomal amphotericin B; D003840:Deoxycholic Acid; D000666:Amphotericin B; C059765:amphotericin B, deoxycholate drug combination; D002784:Cholesterol