Alternation of Organ-Specific Exposure in LPS-Induced Pneumonia Mice after the Inhalation of Tetrandrine Is Governed by Metabolizing Enzyme Suppression and Lysosomal Trapping

The objective of the present study was to define whether inhaled tetrandrine (TET) could be a promising way to achieve the local effect on its therapeutic efficacy based on biodistribution features using the LPS-treated acute lung injury (ALI) model. The tissue distribution profiles of inhaled TET i...

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Veröffentlicht in:International journal of molecular sciences 2022-11, Vol.23 (21), p.12948
Hauptverfasser: Wang, Furun, Jiang, Xue, Yang, Zengxu, Fu, Shuang, Yao, Shi, Wang, Lingchao, Lv, Yue, Zhang, Wenpeng, Ding, Rigao, Zhuang, Xiaomei
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container_issue 21
container_start_page 12948
container_title International journal of molecular sciences
container_volume 23
creator Wang, Furun
Jiang, Xue
Yang, Zengxu
Fu, Shuang
Yao, Shi
Wang, Lingchao
Lv, Yue
Zhang, Wenpeng
Ding, Rigao
Zhuang, Xiaomei
description The objective of the present study was to define whether inhaled tetrandrine (TET) could be a promising way to achieve the local effect on its therapeutic efficacy based on biodistribution features using the LPS-treated acute lung injury (ALI) model. The tissue distribution profiles of inhaled TET in normal and ALI mouse models showed that pulmonary inflammation led to an altered distribution in a tissue-specific way. More TET accumulated in almost all tissues including in the blood. Among them, the increased exposure in the lungs was significantly higher than in the other tissues. However, there was a negative increase in the brain. In vitro turnover rates of TET in mouse liver microsomes (MLM) from normal and LPS-treated mice showed significant differences. In the presence of NADPH, TET demonstrated relatively low hepatic clearance (89 mL/h/kg) in that of normal MLM (140 mL/h/kg). Intracellular uptakes of TET in A549, HepG2, RAW264.7, and C8-D1A cells were significantly inhibited by monensin, indicating that the intracellular accumulation of TET is driven by lysosomal trapping. However, in the presence of LPS, only the lysosomal pH partitioning of TET in A549 cell lines increased (~30%). Bidirectional transport of TET across LLC-PK1 cell expressing MDR1 showed that MDR1 is responsible for the low brain exposure via effluxion (ER = 32.46). From the observed overall agreement between the in vitro and in vivo results, we concluded that the downregulation of the CYP3A together with strengthened pulmometry lysosomal trapping magnified the retention of inhaled TET in the lung. These results therefore open the possibility of prolonging the duration of the local anti-inflammation effect against respiratory disorders.
doi_str_mv 10.3390/ijms232112948
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Bidirectional transport of TET across LLC-PK1 cell expressing MDR1 showed that MDR1 is responsible for the low brain exposure via effluxion (ER = 32.46). From the observed overall agreement between the in vitro and in vivo results, we concluded that the downregulation of the CYP3A together with strengthened pulmometry lysosomal trapping magnified the retention of inhaled TET in the lung. 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The tissue distribution profiles of inhaled TET in normal and ALI mouse models showed that pulmonary inflammation led to an altered distribution in a tissue-specific way. More TET accumulated in almost all tissues including in the blood. Among them, the increased exposure in the lungs was significantly higher than in the other tissues. However, there was a negative increase in the brain. In vitro turnover rates of TET in mouse liver microsomes (MLM) from normal and LPS-treated mice showed significant differences. In the presence of NADPH, TET demonstrated relatively low hepatic clearance (89 mL/h/kg) in that of normal MLM (140 mL/h/kg). Intracellular uptakes of TET in A549, HepG2, RAW264.7, and C8-D1A cells were significantly inhibited by monensin, indicating that the intracellular accumulation of TET is driven by lysosomal trapping. However, in the presence of LPS, only the lysosomal pH partitioning of TET in A549 cell lines increased (~30%). 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source MDPI - Multidisciplinary Digital Publishing Institute; EZB-FREE-00999 freely available EZB journals; PubMed Central
subjects Animal models
Biodistribution
Cell lines
Coronaviruses
Dengue fever
Disease
Enzymes
Exposure
Infections
Inflammation
Inhalation
Intracellular
Lipopolysaccharides
Lungs
MDR1 protein
Metabolism
Microsomes
Monensin
Permeability
Pharmacokinetics
Pneumonia
Respiration
Testosterone
Tetrandrine
Trapping
Turnover rate
Viral infections
title Alternation of Organ-Specific Exposure in LPS-Induced Pneumonia Mice after the Inhalation of Tetrandrine Is Governed by Metabolizing Enzyme Suppression and Lysosomal Trapping
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