Pharmacokinetics, excretion, and mass balance of ¹⁴C after administration of ¹⁴C-cholesterol labeled AmBisome to healthy volunteers

Amphotericin B (AmB) in small unilamellar liposomes (AmBisome) provides higher plasma concentrations and greater safety than the conventional deoxycholate formulation. The authors compared the disposition of the liposome's drug and cholesterol components by measuring AmB and radioactivity in plasma, urine, and feces for 1 week after a single 2-hour infusion of ¹⁴C-cholesterol-labeled AmBisome (2 mg/kg, 1 μCi/kg) in healthy adults (4 males, 1 female). The plasma profile of ¹⁴C-cholesterol differed from that of AmB, lacking an initial rapid disappearance phase, having a lower total clearance, and having a volume of distribution (0.13 L/kg) close to that of the plasma compartment. The biphasic disappearance and long plasma half-life (147 h) of ¹⁴C-cholesterol were similar to those of other low-clearance liposomes. This and the low clearance of ¹⁴C-cholesterol from the plasma compartment suggest that it served as a liposome marker. The plasma drug-lipid ratio fell during the study, showing that AmB was cleared from plasma more rapidly than cholesterol or liposomes and suggesting that the composition of the liposomes changed over time. ¹⁴C-radioactivity was recovered mainly in the feces (9.5% of dose), consistent with the catabolism of cholesterol to bile salts. Combined fecal and renal clearances were < 18% of total clearance, suggesting that most of the liposomal drug and lipid remained in the body 1 week after dosing. Thus, AmBisome remains in the circulation for an extended period of time while releasing AraB, resulting in its markedly altered pharmacokinetic and safety profiles.