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

Amphotericin B (AmB) in small unilamellar liposomes (AmBisome) provides hig her plasma concentrations and greater safety than the conventional deoxycho late formulation. The authors compared the disposition of the liposome's dr ug and cholesterol components by measuring AmB and radioactivity in plasma, urine, and fences for 1 week after a single 2-hour infusion of C-14-choles terol-labeled AmBisome (2 mg/kg, 1 mu Ci/kg) in healthy adults (4 males, 1 female). The plasma profile of C-14-cholesterol differed from that of AmB, locking an initial rapid disappearance phase, having a lower total clearanc e, and having a volume of distribution (0.13 L/kg) close to that of the pla sma compartment. The biphasic disappearance and long plasma half-life (147 h) of C-14-cholesterol were similar to those of other low-clearance liposom es. This and the low clearance of C-14-cholesterol from the plasma compartm ent suggest that it served as a liposome marker. The plasma drug-lipid rati o fell during the study, showing that AmB was cleared from plasma more rapi dly than cholesterol or liposomes and suggesting that the composition of th e liposomes changed over time. C-14-radioactivity was recovered mainly in t he feces (9.5% of dose), consistent with the catabolism of cholesterol to b ile salts. Combined fecal and renal clearances were < 18% of total clearanc e, suggesting that most of the liposomal drug and lipid remained in the bod y 1 week after dosing. Thus, AmBisome remains in the circulation for an ext ended Period of time while releasing AmB, resulting in its markedly altered pharmacokinetic and safety profiles. (C) 2001 the American College of Clin ical Pharmacology.