两性霉素B及其脂质制剂的肺内药代动力学分区特征

Compartmentalized intrapulmonary pharmacokinetics of amphotericin B and its lipid formulations.

作者信息

Groll Andreas H, Lyman Caron A, Petraitis Vidmantas, Petraitiene Ruta, Armstrong Derek, Mickiene Diana, Alfaro Raul M, Schaufele Robert L, Sein Tin, Bacher John, Walsh Thomas J

机构信息

Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD 20892, USA.

出版信息

Antimicrob Agents Chemother. 2006 Oct;50(10):3418-23. doi: 10.1128/AAC.00241-06.

DOI:10.1128/AAC.00241-06

PMID:17005824

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1610093/

Abstract

We investigated the compartmentalized intrapulmonary pharmacokinetics of amphotericin B and its lipid formulations in healthy rabbits. Cohorts of three to seven noninfected, catheterized rabbits received 1 mg of amphotericin B deoxycholate (DAMB) per kg of body weight or 5 mg of either amphotericin B colloidal dispersion (ABCD), amphotericin B lipid complex (ABLC), or liposomal amphotericin B (LAMB) per kg once daily for a total of 8 days. Following sparse serial plasma sampling, rabbits were sacrificed 24 h after the last dose, and epithelial lining fluid (ELF), pulmonary alveolar macrophages (PAM), and lung tissue were obtained. Pharmacokinetic parameters in plasma were derived by model-independent techniques, and concentrations in ELF and PAM were calculated based on the urea dilution method and macrophage cell volume, respectively. Mean amphotericin B concentrations +/- standard deviations (SD) in lung tissue and PAM were highest in ABLC-treated animals, exceeding concurrent plasma levels by 70- and 375-fold, respectively (in lung tissue, 16.24 +/- 1.62 versus 2.71 +/- 1.22, 6.29 +/- 1.17, and 6.32 +/- 0.57 microg/g for DAMB-, ABCD-, and LAMB-treated animals, respectively [P = 0.0029]; in PAM, 89.1 +/- 37.0 versus 8.92 +/- 2.89, 5.43 +/- 1.75, and 7.52 +/- 2.50 mug/ml for DAMB-, ABCD-, and LAMB-treated animals, respectively [P = 0.0246]). By comparison, drug concentrations in ELF were much lower than those achieved in lung tissue and PAM. Among the different cohorts, the highest ELF concentrations were found in LAMB-treated animals (2.28 +/- 1.43 versus 0.44 +/- 0.13, 0.68 +/- 0.27, and 0.90 +/- 0.28 microg/ml in DAMB-, ABCD-, and ABLC-treated animals, respectively [P = 0.0070]). In conclusion, amphotericin B and its lipid formulations displayed strikingly different patterns of disposition in lungs 24 h after dosing. Whereas the disposition of ABCD was overall not fundamentally different from that of DAMB, ABLC showed prominent accumulation in lung tissue and PAM, while LAMB achieved the highest concentrations in ELF.

摘要

我们研究了两性霉素B及其脂质制剂在健康兔体内的肺内药代动力学分布情况。将3至7只未感染且已插管的兔分为几组，每组动物每日每千克体重接受1毫克去氧胆酸盐两性霉素B（DAMB），或5毫克两性霉素B胶体分散体（ABCD）、两性霉素B脂质复合物（ABLC）或脂质体两性霉素B（LAMB），共给药8天。在进行稀疏的系列血浆采样后，于末次给药后24小时处死兔子，获取上皮衬液（ELF）、肺泡巨噬细胞（PAM）和肺组织。血浆中的药代动力学参数通过非模型依赖技术得出，ELF和PAM中的浓度分别基于尿素稀释法和巨噬细胞体积进行计算。在接受ABLC治疗的动物中，肺组织和PAM中的两性霉素B平均浓度±标准差（SD）最高，分别比同期血浆水平高出70倍和375倍（在肺组织中，接受DAMB、ABCD和LAMB治疗的动物分别为16.24±1.62、6.29±1.17和6.32±0.57微克/克，与2.71±1.22微克/克相比[P = 0.0029]；在PAM中，接受DAMB、ABCD和LAMB治疗的动物分别为89.1±37.0、5.43±1.75和7.52±2.50微克/毫升，与8.92±2.89微克/毫升相比[P = 0.0246]）。相比之下，ELF中的药物浓度远低于肺组织和PAM中的浓度。在不同组中，接受LAMB治疗的动物ELF浓度最高（接受DAMB、ABCD和ABLC治疗的动物分别为2.28±1.43、0.44±0.13和0.68±0.27微克/毫升，与0.90±0.28微克/毫升相比[P = 0.0070]）。总之，给药24小时后，两性霉素B及其脂质制剂在肺内呈现出截然不同的分布模式。虽然ABCD的分布总体上与DAMB没有根本差异，但ABLC在肺组织和PAM中显示出显著蓄积，而LAMB在ELF中达到最高浓度。