Abstract
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.
Key words
AmBisome® - Antifungal drugs - CAS 1397-89-3 - Liposomal amphotericin B, metabolism,
pharmacokinetics
