Inhibition of P-glycoprotein - Mediated Efflux of Digoxinand Its Metabolites by Macrolide Antibiotics
This study was conducted to determine the rate of P-glycoprotein (P-gp) mediated efflux of digoxin analogues and metabolites, and to assess the effects of macrolide antibiotics on this efflux. Bidirectional transport studies were conducted using our Caco-2 sub clone with high P-gp expression (CLEFF9...
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| Format: | Journal Article |
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The Japanese Pharmacological Society
2010
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| Online Access: | http://hdl.handle.net/20.500.11937/17778 |
| _version_ | 1848749555515916288 |
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| author | Hughes, Jeffery Crowe, Andrew |
| author2 | Kim Brosen |
| author_facet | Kim Brosen Hughes, Jeffery Crowe, Andrew |
| author_sort | Hughes, Jeffery |
| building | Curtin Institutional Repository |
| collection | Online Access |
| description | This study was conducted to determine the rate of P-glycoprotein (P-gp) mediated efflux of digoxin analogues and metabolites, and to assess the effects of macrolide antibiotics on this efflux. Bidirectional transport studies were conducted using our Caco-2 sub clone with high P-gp expression (CLEFF9). HPLC methods were employed to measure drug transport. All digoxin metabolites were P-gp substrates, although digoxin had the greatest efflux ratio. Erythromycin had no effect on the transport of digoxin, maintaining a Basolateral to apical efflux ratio of 14.8, although it did reduce the efflux ratio of dihydrodigoxin and digoxigenin by 34% and 43%, respectively. Azithromycin also had little effect on the transport of digoxin or any of its metabolites. In contrast, clarithromycin and roxithromycin almost eliminated basolateral targeted efflux. Using paclitaxel as a known P-gp substrate, erythromycin demonstrated only partial P-gp inhibitory capacity maintaining an efflux ratio over 100. In contrast, clarithromycin and roxithromycin were 10 fold greater P-gp inhibitors. Clarithromycin and roxithromycin are likely to exhibit drug interactions with digoxin via inhibition of efflux mechanisms. Azithromycin appears to have little influence on P-gp mediated digoxin absorption or excretion and would be the safest macrolide to use concurrently with oral digoxin. |
| first_indexed | 2025-11-14T07:22:48Z |
| format | Journal Article |
| id | curtin-20.500.11937-17778 |
| institution | Curtin University Malaysia |
| institution_category | Local University |
| last_indexed | 2025-11-14T07:22:48Z |
| publishDate | 2010 |
| publisher | The Japanese Pharmacological Society |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | curtin-20.500.11937-177782023-01-13T07:56:29Z Inhibition of P-glycoprotein - Mediated Efflux of Digoxinand Its Metabolites by Macrolide Antibiotics Hughes, Jeffery Crowe, Andrew Kim Brosen Michael Mulvany clarithromycin Caco-2 P-glycoprotein erythromycin azithromycin This study was conducted to determine the rate of P-glycoprotein (P-gp) mediated efflux of digoxin analogues and metabolites, and to assess the effects of macrolide antibiotics on this efflux. Bidirectional transport studies were conducted using our Caco-2 sub clone with high P-gp expression (CLEFF9). HPLC methods were employed to measure drug transport. All digoxin metabolites were P-gp substrates, although digoxin had the greatest efflux ratio. Erythromycin had no effect on the transport of digoxin, maintaining a Basolateral to apical efflux ratio of 14.8, although it did reduce the efflux ratio of dihydrodigoxin and digoxigenin by 34% and 43%, respectively. Azithromycin also had little effect on the transport of digoxin or any of its metabolites. In contrast, clarithromycin and roxithromycin almost eliminated basolateral targeted efflux. Using paclitaxel as a known P-gp substrate, erythromycin demonstrated only partial P-gp inhibitory capacity maintaining an efflux ratio over 100. In contrast, clarithromycin and roxithromycin were 10 fold greater P-gp inhibitors. Clarithromycin and roxithromycin are likely to exhibit drug interactions with digoxin via inhibition of efflux mechanisms. Azithromycin appears to have little influence on P-gp mediated digoxin absorption or excretion and would be the safest macrolide to use concurrently with oral digoxin. 2010 Journal Article http://hdl.handle.net/20.500.11937/17778 10.1254/jphs.10109FP The Japanese Pharmacological Society fulltext |
| spellingShingle | clarithromycin Caco-2 P-glycoprotein erythromycin azithromycin Hughes, Jeffery Crowe, Andrew Inhibition of P-glycoprotein - Mediated Efflux of Digoxinand Its Metabolites by Macrolide Antibiotics |
| title | Inhibition of P-glycoprotein - Mediated Efflux of Digoxinand Its Metabolites by Macrolide Antibiotics |
| title_full | Inhibition of P-glycoprotein - Mediated Efflux of Digoxinand Its Metabolites by Macrolide Antibiotics |
| title_fullStr | Inhibition of P-glycoprotein - Mediated Efflux of Digoxinand Its Metabolites by Macrolide Antibiotics |
| title_full_unstemmed | Inhibition of P-glycoprotein - Mediated Efflux of Digoxinand Its Metabolites by Macrolide Antibiotics |
| title_short | Inhibition of P-glycoprotein - Mediated Efflux of Digoxinand Its Metabolites by Macrolide Antibiotics |
| title_sort | inhibition of p-glycoprotein - mediated efflux of digoxinand its metabolites by macrolide antibiotics |
| topic | clarithromycin Caco-2 P-glycoprotein erythromycin azithromycin |
| url | http://hdl.handle.net/20.500.11937/17778 |