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Association between the number of coadministered P-glycoprotein inhibitors and serum digoxin levels in patients on therapeutic drug monitoring
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. klin farm. (osteoporos)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. (Ortopedi)
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2004 (English)In: BMC Medicine, ISSN 1741-7015, E-ISSN 1741-7015, Vol. 2, 8- p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: The ABC transporter P-glycoprotein (P-gp) is recognized as a site for drug-drug interactions and provides a mechanistic explanation for clinically relevant pharmacokinetic interactions with digoxin. The question of whether several P-gp inhibitors may have additive effects has not yet been addressed. METHODS: We evaluated the effects on serum concentrations of digoxin (S-digoxin) in 618 patients undergoing therapeutic drug monitoring. P-gp inhibitors were classified as Class I, with a known effect on digoxin kinetics, or Class II, showing inhibition in vitro but no documented effect on digoxin kinetics in humans. Mean S-digoxin values were compared between groups of patients with different numbers of coadministered P-gp inhibitors by a univariate and a multivariate model, including the potential covariates age, sex, digoxin dose and total number of prescribed drugs. RESULTS: A large proportion (47%) of the digoxin patients undergoing therapeutic drug monitoring had one or more P-gp inhibitor prescribed. In both univariate and multivariate analysis, S-digoxin increased in a stepwise fashion according to the number of coadministered P-gp inhibitors (all P values < 0.01 compared with no P-gp inhibitor). In multivariate analysis, S-digoxin levels were 1.26 +/- 0.04, 1.51 +/- 0.05, 1.59 +/- 0.08 and 2.00 +/- 0.25 nmol/L for zero, one, two and three P-gp inhibitors, respectively. The results were even more pronounced when we analyzed only Class I P-gp inhibitors (1.65 +/- 0.07 for one and 1.83 +/- 0.07 nmol/L for two). CONCLUSIONS: Polypharmacy may lead to multiple drug-drug interactions at the same site, in this case P-gp. The S-digoxin levels increased in a stepwise fashion with an increasing number of coadministered P-gp inhibitors in patients taking P-gp inhibitors and digoxin concomitantly. As coadministration of digoxin and P-gp inhibitors is common, it is important to increase awareness about P-gp interactions among prescribing clinicians.

Place, publisher, year, edition, pages
2004. Vol. 2, 8- p.
Keyword [en]
Analysis of Variance, Digoxin/*blood/pharmacokinetics, Drug Interactions, Drug Monitoring, Female, Humans, Male, P-Glycoprotein/*antagonists & inhibitors, Polypharmacy, Research Support; Non-U.S. Gov't
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-71417DOI: 10.1186/1741-7015-2-8PubMedID: 15061868OAI: oai:DiVA.org:uu-71417DiVA: diva2:99328
Available from: 2005-08-16 Created: 2005-08-16 Last updated: 2017-11-21Bibliographically approved

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Englund, GunillaHallberg, PärArtursson, PerMichaëlsson, KarlMelhus, Håkan

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