Compartimentalized Intrapulmonary Concentrations of Four Licensed amphotericin B Formulations in Noninfected Rabbits.

A.H. GROLL, C.A. LYMAN, V. PETRAITIS, R. PETRAITIENE, D. ARMSTRONG, D. MICKIENE, R.M. ALFARO, T.J. WALSH

Author address: 

University Children's Hospital, Münster, Germany, National Cancer Institute, Bethesda, MD, Pharm. Dept., Clinical Center, NIH, Bethesda, MD.

Abstract: 

Background: The four licensed amphotericin B (AMB) formulations have different pharmacokinetic properties. Little is known, however, about their comparative disposition in the lung. Methods: Cohorts of 3 to 7 noninfected, catheterized rabbits received therapeutic IV dosages of amphotericin B deoxycholate (DAMB; 1mg/kg) or (5mg/kg) of either amphotericin B colloidal dispersion (ABCD), amphotericin B lipid complex (ABLC) or liposomal amphotericin B (LAMB) QD over 5 min for 8 days. Rabbits were sacrificed 24 h after the last dose, and blood, epithelial lining fluid (ELF), pulmonary alveolar macrophages (PAMs) and lung tissue were obtained. Concentrations of AMB were determined as those of total drug by HPLC. Values for ELF and PAM were calculated based on the urea dilution method and macrophage cell volume, respectively. Results: At 24 hours after the 8th dose, concentrations of AMB in lung tissue and PAMs were highest in ABLC-treated animals, exceeding concurrent plasma levels 70- and 375-fold, respectively. Drug concentrations in ELF were generally much lower than those achieved in lung tissue and PAMs. Among the different cohorts, highest ELF concentrations were found in LAMB-treated animals (table). Cohort Plasma [µg/mL] Lung Tissue [µg/g] PAMs [µg/mL] ELF [µg/mL] DAMB 1 0.34 ±0.02 2.71 ±0.45 8.92 ±1.09 0.44 ±0.05 ABCD 5 0.37 ±0.06 6.29 ±0.58 5.43 ±0.82 0.68 ±0.13 ABLC 5 0.24 ±0.04 16.24 ±0.93 89.15 ±21.37 0.90 ±0.16 LAMB 5 26.4 ±2.47 6.32 ±0.28 7.52 ±1.25 2.28 ±0.71 P value 0.0146 0.0029 0.0246 0.0070 Conclusions: The four licensed amphotericin B formulations displayed strikingly different disposition patterns in the lung. Whereas the disposition of ABCD was overall not fundamentally different to that of
2003

abstract No: 

M-359

Full conference title: 

43rd Interscience Conference on Antimicrobial Agents
    • ICAAC 43rd