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Biodistribution and histopathology studies of amphotericin B sodium deoxycholate sulfate formulation following intratracheal instillation in rat models

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Abstract

Aerosol inhalation of amphotericin B (AmB) can be a clinically compliant way to administer the drug directly to the pulmonary route for treatment as well as prophylaxis of invasive pulmonary aspergillosis (IPA). We report aerosol formulation of AmB using sodium deoxycholate sulfate (SDCS), a lipid carrier synthesized in-house using natural precursor deoxycholic acid. In vitro toxicity was determined by MTT assay. Biodistribution and histopathology in rats were evaluated in targeted organs including the lungs, kidneys, spleen, and liver. No toxicity was observed when lung and kidney cells treated with AmB-SDCS formulations up to 8 μg/mL and minimal toxicity at higher concentration 16 μg/mL, while the Fungizone®-like formulation induced toxicity to lung and kidney cells with viability decreasing from 86 to 41% and 100 to 49%, respectively, when compared with an equivalent concentration of AmB-SDCS. Renal and hepatic markers were raised for Fungizone®-like formulation–treated rats but not for AmB-SDCS formulations following 7 days of regular dosing by intratracheal instillation. AmB concentrations were highest in the lungs (5.4–8.3 μg/g) which were well above minimum inhibitory concentration (MIC) of all Aspergillus species. Plasma concentration was also above MIC (> 2 μg/mL) for all AmB-SDCS formulations in comparison with Fungizone®-like formulation. No evidence of abnormal histopathology was observed in the lungs, liver, spleen, and kidneys for all AmB-SDCS formulations but was observed for the group treated with Fungizone®-like formulation. It is concluded that AmB-SDCS formulations can be efficiently administered via intratracheal instillation with no evidence of toxicity and may find great value in the treatment as well as prophylaxis of IPA through inhalation route.

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Funding

This research was supported by a grant from the 2014 scholarship awards for Masters and Ph.D. studies under Thailand’s Education Hub for Southern Region of ASEAN countries (TEH-AC) and National Research Council of Thailand (PHA610372S), Department of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, Prince of Songkla University.

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Authors and Affiliations

  1. Drug Delivery System Excellence Centre, Department of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat Yai, Songkhla, 90112, Thailand

    Faisal Usman & Teerapol Srichana

  2. Department of Anatomy, Faculty of Science, Prince of Songkla University, Hat Yai, Songkhla, 90112, Thailand

    Jongdee Nopparat

  3. ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia

    Ibrahim Javed

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  1. Faisal Usman
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  4. Teerapol Srichana
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Correspondence to Teerapol Srichana.

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Ethical approval

Biodistribution and histopathology studies were performed that strictly followed the ethical guidelines approved by the animal ethics committee, Prince of Songkla University (MOE 0521.11/522, Ref. 08/2015).

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Usman, F., Nopparat, J., Javed, I. et al. Biodistribution and histopathology studies of amphotericin B sodium deoxycholate sulfate formulation following intratracheal instillation in rat models. Drug Deliv. and Transl. Res. 10, 59–69 (2020). https://doi.org/10.1007/s13346-019-00662-x

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  • DOI: https://doi.org/10.1007/s13346-019-00662-x

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