Dose-dependent pharmacokinetics of amphotericin B lipid complex in rabbits

Citation
Tj. Walsh et al., Dose-dependent pharmacokinetics of amphotericin B lipid complex in rabbits, ANTIM AG CH, 44(8), 2000, pp. 2068-2076
Citations number
18
Categorie Soggetti
Microbiology
Journal title
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
ISSN journal
00664804 → ACNP
Volume
44
Issue
8
Year of publication
2000
Pages
2068 - 2076
Database
ISI
SICI code
0066-4804(200008)44:8<2068:DPOABL>2.0.ZU;2-U
Abstract
Amphotericin B lipid complex (ABLC) was recently approved by the Food and D rug Administration for treatment of patients with invasive fungal infection s who are intolerant of or refractory to conventional amphotericin B therap y. Little is known, however, about the pharmacokinetics of this new antifun gal compound. We therefore investigated the pharmacokinetics of ABLC in com parison with those of conventional desoxycholate amphotericin B (DAmB) in r abbits. The pharmacokinetics of DAmB in a rabbit model were similar to thos e previously reported in humans. The pharmacokinetics of ABLC differed subs tantially from those of DAmB. Plasma amphotericin B levels following ABLC a dministration were 10 times lower than those following administration of an equal dosage of DAmB. The levels of ABLC in whole blood were approximately 40 times greater than those in plasma. The ABLC model differed from the DA mB model by (i) a dose- and time-dependent uptake and return between the pl asma compartment and apparent cellular components of the blood-sediment com partment and (ii) time-dependent tissue uptake and return to plasma from se rially connected compartments. Following infusion of ABLC, there was a nonl inear uptake into the apparent cellular components of the blood-sediment co mpartment. This uptake was related to the reciprocal of the integral of the total amount of drug infused (i.e., the more drug infused the greater the fractional uptake between 0.5 and 5 mg/kg of body weight for ABLC). The tra nsfer of drug from plasma to the cellular components of the blood-sediment compartment resulted in initial uptake followed by rapid redistribution bac k to the plasma. The study describes a detailed model of the pharmacokineti cs of ABLC and characterizes a potential role of the cellular components of the blood-sediment compartment in the distribution of this new antifungal compound in tissue.