Objective To investigate the effects ofamiodarone （AMD） on simvastatin （SV） in human liver microsomes and the possible underlying mechanisms. Methods Time-, NADPH- and concentration-dependent inhibitions were test...Objective To investigate the effects ofamiodarone （AMD） on simvastatin （SV） in human liver microsomes and the possible underlying mechanisms. Methods Time-, NADPH- and concentration-dependent inhibitions were tested in HLM. The logarithm of relative inhibition values was plotted versus preincubation time （0, 5, 10, 15, 20min） for a series concentration of AMD used （0, 2, 5, 25, 50 umol/L）, and the slopes determined by linear regression. These slope values represente the observed inactivation rate constants （kobs ）. A double-reciprocal plot was then constructed using the reciprocal of the kobs （y-axis） and the reciprocal of the associated inhibitor concentration （x-axis） to estimate the values of kinact and K1, which were two principal kinetic constants that were specific for mechanism-based inhibition （MBI）.drug-drug interactions （DDI） potential was predicted based on in vitro data and by using the in vitro-in vivo extrapolation. Results The time-, concentration- and NADPH-dependent characteristics confirmed that when SV was the substrate of CYP3A4, the inhibition of AMD to CYP3A4 is MBI. KI and kinact value were calculated to be 5.1umol/L and 0.018minL The CLant of SV was reduced 2.96-5.63 fold when it was administrated with AMD. Conclusion Based on the results, AMD would inhibit SV metabolism via the mechanism-based manner, which would lead to DDI when they are taken together. Careful clinical observation is recommended when AMD and SV have to be simultaneously prescribed.展开更多
To explore the target of action of LHQW-XYS on the main components of COVID-19 olfactory impairment by using network pharmacological methods and try to reveal its mechanism of action in the treatment related to COVID-...To explore the target of action of LHQW-XYS on the main components of COVID-19 olfactory impairment by using network pharmacological methods and try to reveal its mechanism of action in the treatment related to COVID-19 induced olfactory impairment,we used the TCMSP platform to obtain potential active ingredients through oral utilization and drug-like properties screening;the Swiss TargetPrediction platform to predict the targets of the active ingredients and construct a drug-ingredient-target network,and then obtained the gene targets of COVID-19 olfactory injury through GeneCards,OMIM,and TTD platforms to intersect the drug targets and disease genes to obtain common targets.The drug targets and disease genes were intersected to obtain common targets.STRING and Cytoscape 3.8.2 software were used to construct the target-disease gene PPI network,screen the key targets and core gene clusters,and analyze the key targets by GO and KEGG enrichment analyses with the help of the Metascape platform,and then map the screened core active ingredients and their targets into the pathway to construct the core active ingredients-targets-pathway network.The core active ingredient-target-pathway network was constructed,and finally,molecular docking was carried out.The results showed that there were 4669 potential targets,5609 disease targets,and 17 drug-disease cross-targets for the active ingredients of LHQW-XYS.The GO and KEGG enrichment analyses indicated that the mechanism of LHQW-XYS in the treatment of olfactory impairment in COVID-19 may be due to the regulation of related signaling pathways,such as Serotonergic synapse and Regulation of lipolysis in adipocytes.Molecular docking showed that six active components(quercetin,luteolin,kaempferol,7-methoxy-2-methylisoflavone,wogonin,medicarpin)and two key genes(PTGS2,PPARG)had good binding properties.In the end,we conclude that LHQW-XYS may act on Serotonergic synapse and Regulation of lipolysis in adipocyte pathways to achieve anti-COVID-19 olfactory impairment-associated effects.展开更多
文摘Objective To investigate the effects ofamiodarone （AMD） on simvastatin （SV） in human liver microsomes and the possible underlying mechanisms. Methods Time-, NADPH- and concentration-dependent inhibitions were tested in HLM. The logarithm of relative inhibition values was plotted versus preincubation time （0, 5, 10, 15, 20min） for a series concentration of AMD used （0, 2, 5, 25, 50 umol/L）, and the slopes determined by linear regression. These slope values represente the observed inactivation rate constants （kobs ）. A double-reciprocal plot was then constructed using the reciprocal of the kobs （y-axis） and the reciprocal of the associated inhibitor concentration （x-axis） to estimate the values of kinact and K1, which were two principal kinetic constants that were specific for mechanism-based inhibition （MBI）.drug-drug interactions （DDI） potential was predicted based on in vitro data and by using the in vitro-in vivo extrapolation. Results The time-, concentration- and NADPH-dependent characteristics confirmed that when SV was the substrate of CYP3A4, the inhibition of AMD to CYP3A4 is MBI. KI and kinact value were calculated to be 5.1umol/L and 0.018minL The CLant of SV was reduced 2.96-5.63 fold when it was administrated with AMD. Conclusion Based on the results, AMD would inhibit SV metabolism via the mechanism-based manner, which would lead to DDI when they are taken together. Careful clinical observation is recommended when AMD and SV have to be simultaneously prescribed.
基金National Natural Science Foundation of China General Project(Grant No.82374195).
文摘To explore the target of action of LHQW-XYS on the main components of COVID-19 olfactory impairment by using network pharmacological methods and try to reveal its mechanism of action in the treatment related to COVID-19 induced olfactory impairment,we used the TCMSP platform to obtain potential active ingredients through oral utilization and drug-like properties screening;the Swiss TargetPrediction platform to predict the targets of the active ingredients and construct a drug-ingredient-target network,and then obtained the gene targets of COVID-19 olfactory injury through GeneCards,OMIM,and TTD platforms to intersect the drug targets and disease genes to obtain common targets.The drug targets and disease genes were intersected to obtain common targets.STRING and Cytoscape 3.8.2 software were used to construct the target-disease gene PPI network,screen the key targets and core gene clusters,and analyze the key targets by GO and KEGG enrichment analyses with the help of the Metascape platform,and then map the screened core active ingredients and their targets into the pathway to construct the core active ingredients-targets-pathway network.The core active ingredient-target-pathway network was constructed,and finally,molecular docking was carried out.The results showed that there were 4669 potential targets,5609 disease targets,and 17 drug-disease cross-targets for the active ingredients of LHQW-XYS.The GO and KEGG enrichment analyses indicated that the mechanism of LHQW-XYS in the treatment of olfactory impairment in COVID-19 may be due to the regulation of related signaling pathways,such as Serotonergic synapse and Regulation of lipolysis in adipocytes.Molecular docking showed that six active components(quercetin,luteolin,kaempferol,7-methoxy-2-methylisoflavone,wogonin,medicarpin)and two key genes(PTGS2,PPARG)had good binding properties.In the end,we conclude that LHQW-XYS may act on Serotonergic synapse and Regulation of lipolysis in adipocyte pathways to achieve anti-COVID-19 olfactory impairment-associated effects.
