Disposition of amphotericin B in the isolated perfused rat liver.
The hepatic disposition and biliary excretion of amphotericin B were investigated in the isolated perfused rat liver (IPRL). Bolus dose of 50 microg, 99 microg and 198 microg amphotericin B in lipoprotein-free perfusate and 198 microg amphotericin B in perfusate with 1 microM high-density lipoprotein (HDL) or 1 microM 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 (CL(H)) 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.
Faculty of Pharmacy, University of Sydney, NSW 2006, Australia.
Ying
Y
Hong
Iqbal
I
Ramzan
Andrew J
AJ
McLachlan
D000666:Amphotericin B / Q000493:pharmacokinetics*; D000818:Animals; D000935:Antifungal Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001646:Bile / Q000378:metabolism; D008076:Cholesterol, HDL / Q000378:metabolism; D008078:Cholesterol, LDL / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004355:Drug Stability; D006207:Half-Life; D008099:Liver / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
D000935:Antifungal Agents; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D000666:Amphotericin B