Abstract
When propafenone is given with digoxin, digoxin serum concentrations increase. Although the digoxin-propafenone interaction is well known clinically, the mechanism by which propafenone interferes with digoxin elimination is unclear. To test the hypothesis that propafenone or one or both of its two major metabolites, 5-hydroxypropafenone (5-OHP) and N-depropylpropafenone (NDPP), inhibit the P-glycoprotein-mediated net renal tubular secretion of digoxin, we examined the transport of digoxin and the well-studied P-glycoprotein substrate vinblastine across confluent Madin-Darby canine kidney cell monolayers in the absence and presence of propafenone, 5-OHP and NDPP. Propafenone and its two major metabolites significantly inhibit the secretory flux of digoxin and vinblastine (propafenone > 5-OHP ≫ NDPP). Despite decreases in net transport, cellular digoxin accumulation did not decrease, suggesting that neither propafenone nor its metabolites prohibited digoxin from entering the cells at the basolateral side. NDPP, but not 5-OHP, was detected after 48 hr of incubation of the cells with propafenone alone. When the cells were incubated with propafenone or 5-OHP, apical accumulation of 5-OHP, but neither propafenone nor NDPP, against a concentration gradient was observed. These findings are consistent with the hypothesis that the digoxin-propafenone interaction results from the inhibition of the renal tubular transport of digoxin by propafenone and its metabolites. Our data suggest that propafenone is an inhibitor of P-glycoprotein, whereas 5-OHP is a possible substrate.
Footnotes
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Send reprint requests to: Dr. Shinya Ito, Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada, M5G 1X8.
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↵1 This work was supported by Medical Research Council Grant MT 8544. C.W. is funded by the Canadian Cystic Fibrosis Foundation. G.K. is a Career Scientist (Ontario Ministry of Health).
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↵2 S. Ito, C. Woodland, and B. Sarkadi, unpublished observations.
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↵4 C. Woodland, unpublished observations.
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↵5 C. Woodland and S. Ito, unpublished observations.
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↵3 S. Ito, C. Woodland, and B. Sarkadi, unpublished observations.
- Abbreviations:
- MDR
- multidrug resistance
- 5-OHP
- 5-hydroxypropafenone
- NDPP
- N-depropylpropafenone
- MDCK
- Madin-Darby canine kidney
- α-MEM/FBS
- α-minimum essential medium plus 10% fetal bovine serum
- PBS-G
- phosphate-buffered saline containing 5 mM glucose and 0.02% albumin
- TEA
- tetraethylammonium
- Received December 20, 1996.
- Accepted June 2, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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