Hepatobiliary disposition of liposomal amphotericin B in the isolated perfused rat liver.

The hepatic distribution, biliary excretion, and mass balance of liposomal amphotericin B (L-AmB) were investigated in recirculated isolated perfused rat liver. The results were compared with those from the conventional AmB formulation, amphotericin B deoxycholate (D-AmB). L-AmB was introduced as a bolus into the perfusate reservoir, at doses of 1000, 4000, and 8000 mug, to achieve therapeutically relevant concentrations. AmB concentrations in perfusate, ultrafiltrate, bile, and liver homogenate over 120 min were measured using a validated high-performance liquid chromatography assay. AmB hepatic disposition in isolated perfused rat liver after L-AmB bolus was characterized by a higher recovery in perfusate (81.7 +/- 9.4%, n = 13) and a significant decrease in hepatic distribution (5.9 +/- 2.4% at low dose, 2.4 +/- 0.9% at medium dose, and 1.9 +/- 0.7% at high dose) compared with D-AmB (32.2 +/- 4.5% in perfusate, 52.1 +/- 8.2% in liver at the dose of 198 microg). Tissue-to-perfusate partition coefficient of L-AmB calculated at 120 min decreased dramatically with the dose and was approximately 100-fold less than that achieved with D-AmB at the high dose (0.17 +/- 0.11 in L-AmB versus 15.82 +/- 6.43 in D-AmB). AmB displayed negligible biliary excretion, representing <0.1% of the dose administered with L-AmB. Hepatic uptake clearance of L-AmB (CL(H,uptake)) decreased with the increase in perfusate area under the curve at each dose. The relationship between perfusate area under the curve and CL(H,uptake) was described by a parallel hepatic uptake clearance model. In conclusion, liposomal encapsulation significantly alters the hepatobiliary disposition of AmB; the ability of liposomes to sequester AmB and the dose-dependent hepatic uptake clearance may account for dose-form-dependent differences in AmB pharmacokinetics. (c) 2004 Wiley-Liss, Inc.