两性霉素B脂质制剂的肺部摄取与蓄积

Pulmonary extraction and accumulation of lipid formulations of amphotericin B.

作者信息

Matot I, Pizov R

机构信息

Department of Anesthesiology and Critical Care Medicine, Hadassah University Medical Center, The Hebrew University of Jerusalem, Israel.

出版信息

Crit Care Med. 2000 Jul;28(7):2528-32. doi: 10.1097/00003246-200007000-00056.

DOI:10.1097/00003246-200007000-00056

PMID:10921589

Abstract

OBJECTIVE

To compare single-dose first pass uptake and accumulation of conventional amphotericin B (cAmB), liposomal amphotericin B (L-AmB), and amphotericin B lipid complex (ABLC) by the intact feline lungs.

DESIGN

Prospective, controlled animal study.

SETTING

Experimental laboratory in a university teaching hospital.

SUBJECTS

A total of 31 spontaneously breathing, anesthetized cats.

INTERVENTIONS

The pulmonary uptake of cAmB, L-AmB, and ABLC during a single passage through the pulmonary circulation, and the pulmonary retention of these drugs were studied after a bolus [cAmB, L-AmB, and ABLC, 1 mg/kg (n = 9 each) and ABLC, 5 mg/kg (n = 4)] administration into the right ventricle. The amount of drug taken up by the lung during the first pass was measured from double indicator-dilution outflow curves. Animals were killed 30 mins (cAmB, n = 4; L-AmB, n = 4), 1 hr (cAmB, n = 5; L-AmB, n = 5; ABLC, n = 5), or 6 hrs (ABLC, 1 mg/kg, n = 4; 5 mg/kg, n = 4) after drug administration.

MEASUREMENTS AND MAIN RESULTS

The first-pass uptake of cAmB, L-AmB, and ABLC (mean +/- sD) by the lung was 73%+/-5%, 69%+/-8%, and 82%+/-6% of the injected dose (1 mg/kg), respectively (p > .05). ABLC (1 mg/kg) exhibited prolonged retention in the lung; 23% and 15% of the injected dose of ABLC remained in the lung 1 hr and 6 hrs after its administration, respectively. In contrast, cAmB and L-AmB exhibited rapid back diffusion of the drug out of the lung. After 30 mins, only 4% of the administered cAmB and L-AmB remained in the lung and after 1 hr only 1% to 2% was retained. Increasing the dose of ABLC from 1 mg/kg to 5 mg/kg did not alter pulmonary extraction of the drug; however, compared with the lower dose (1 mg/kg), higher concentrations of the drug were found in the lung 6 hrs after its administration.

CONCLUSIONS

The results demonstrate a substantial extraction and accumulation of ABLC by the lung. This affinity for the lungs may have clinical implications for treating fungal infections that primarily involve the lung. Further studies are required to confirm the potential clinical relevance of these data.

摘要

目的

比较传统两性霉素B（cAmB）、脂质体两性霉素B（L-AmB）和两性霉素B脂质复合物（ABLC）在完整猫肺中的单剂量首过摄取和蓄积情况。

设计

前瞻性对照动物研究。

地点

大学教学医院的实验实验室。

对象

总共31只自主呼吸、麻醉的猫。

干预措施

通过右心室单次推注给药[cAmB、L-AmB和ABLC，1mg/kg（每组n = 9只）和ABLC，5mg/kg（n = 4只）]后，研究cAmB、L-AmB和ABLC在肺循环单次通过期间的肺摄取情况，以及这些药物在肺中的潴留情况。首过期间肺摄取的药物量通过双指示剂稀释流出曲线测量。给药后30分钟（cAmB，n = 4只；L-AmB，n = 4只）、1小时（cAmB，n = 5只；L-AmB，n = 5只；ABLC，n = 5只）或6小时（ABLC，1mg/kg，n = 4只；5mg/kg，n = 4只）处死动物。

测量指标和主要结果

肺对cAmB、L-AmB和ABLC的首过摄取量（均值±标准差）分别为注射剂量（1mg/kg）的73%±5%、69%±8%和82%±6%（p>.05）。ABLC（1mg/kg）在肺中的潴留时间延长；给药后1小时和6小时分别有23%和15%的注射剂量的ABLC留在肺中。相比之下，cAmB和L-AmB在肺中的药物迅速反向扩散。30分钟后，仅4%的给药cAmB和L-AmB留在肺中，1小时后仅保留1%至2%。将ABLC的剂量从1mg/kg增加到5mg/kg并未改变药物的肺摄取率；然而，与较低剂量（1mg/kg）相比，给药6小时后肺中药物浓度更高。