Pharmacokinetics characterization of liposomal amphotericin B: investigation of clearance process and drug interaction potential.
AmBisome, a liposomal formulation of amphotericin B (CAS 1397-89-3, L-AMB), shows different pharmacokinetics from the conventional formulation, amphotericin B deoxycholate (D-AMB). To characterize the clearance process of L-AMB, the form in which it exists in rat plasma, pharmacokinetics in hepatic or renal failure rats, cellular distribution in rat liver, and placental and milk transfer in rat were investigated. Furthermore, to predict the drug-drug interaction, in vitro metabolism of amphotericin B (AMB) by rat, dog and human liver S9 fraction, and effects of L-AMB on drug-metabolizing enzyme systems were investigated. L-AMB was found to exist stably as a liposomal form in rat plasma without any notable transfer to milk or fetus in rats. After administration to hepatic failure rats, the CLtot of AMB decreased to 1/4 and the Vdss decreased to 1/8 compared with the control rat case. In contrast, after administration to renal failure rats, plasma AUC of AMB did not significantly change compared with sham-operated rats. These data suggest that hepatic clearance is the main determinant of the CLtot for L-AMB. In rat liver, L-AMB was distributed mainly to non-parenchymal cells. In the in vitro metabolism study using liver S9 fraction, no metabolite peaks were observed. After repeated administration of L-AMB to rats, there was no change in parameters related to the drug-metabolising enzyme system in liver microsomes. These data demonstrate that clinically significant metabolism-based drug interaction with L-AMB should be less likely.
Matsui
Satomi
S
Pharmacokinetics Research Laboratories, Dainippon Sumitomo Pharma Co., Ltd., Osaka, Japan.
Imai
Satoki
S
Yabuki
Masashi
M
Komuro
Setsuko
S
D000666:Amphotericin B / Q000493:pharmacokinetics*; D000818:Animals; D000935:Antifungal Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D004285:Dogs; D004337:Drug Carriers; D004347:Drug Interactions; D005260:Female; D006207:Half-Life; D006801:Humans; D066298:In Vitro Techniques; D008081:Liposomes; D008099:Liver / Q000378:metabolism; D017093:Liver Failure / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D008892:Milk / Q000378:metabolism; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D051437:Renal Insufficiency / Q000378:metabolism
D000935:Antifungal Agents; D004337:Drug Carriers; D008081:Liposomes; D000666:Amphotericin B