Disposition of amphotericin B in the isolated perfused rat liver

Abstract

Abstract The hepatic disposition and biliary excretion of amphotericin B were investigated in the isolated perfused rat liver (IPRL). Bolus dose of 50 μg, 99 μg and 198 μg amphotericin B in lipoprotein-free perfusate and 198 μg amphotericin B in perfusate with 1 μM high-density lipoprotein (HDL) or 1 μM low-density lipoprotein (LDL) were examined in the IPRL. Amphotericin B concentration in perfusate was measured using a validated HPLC assay. Amphotericin B was eliminated from the perfusate in a biexponential manner. The hepatic clearance (CLH) increased in proportion to the dose administered (0.27±0.05 mL min−1 at low dose, 0.54±0.23 mL min−1 at medium dose and 1.06±0.24 mL min−1 at high dose), indicating non-linear hepatic disposition of amphotericin B. The hepatic extraction ratio of amphotericin B was very low (0.066±0.015). Tissue-to-perfusion partition coefficient, calculated at 120 min, increased 1.5 fold from 9.8±1.7 at low dose to 15.9±6.4 at high dose, suggesting the significant uptake and extensive retention of amphotericin B in the liver. Biliary excretion made only minor contribution to amphotericin B elimination in the IPRL, representing around 1–3% of the dose administered. No metabolites were detected in perfusate, bile and liver samples. The hepatic disposition of amphotericin B was not affected by the presence of HDL and LDL in the perfusate. In conclusion, the hepatic disposition of amphotericin B demonstrates restrictive elimination and is concentration-dependent, consistent with carrier-mediated uptake, and lipoproteins do not influence amphotericin B hepatobiliary disposition.