Knowledge about mechanisms of interactions makes it possible to predict and prevent pharmacokinetic drug interactions. The MDR1 gene encodes the ABC transporter P-glycoprotein (P-gp), which functions as an efflux pump and is recognized as a site for drug-drug interactions 12345. Several commonly used drugs inhibit P-gp efflux, which can increase gastrointestinal absorption, decrease elimination in the bile and urine, and affect the distribution of drugs to certain compartments, such as the central nervous system (CNS) 2345.

Digoxin has a narrow therapeutic range and is recognized as a high-affinity P-gp substrate 6. Risk factors for digoxin toxicity are well known to clinicians and include advanced age, impaired renal function and low body weight. Despite this, statistics show that unintended digoxin intoxication remains a common problem 7. Digoxin has again become a subject of discussion after recent publications demonstrated sex-based differences in mortality 8 and increased mortality among men with serum concentrations of digoxin (S-digoxin) > 1.5 nmol/L 9. In this context, heightened attention to a patient's S-digoxin level is warranted.

Certain inhibitors of P-gp have been demonstrated to increase S-digoxin levels in healthy volunteers 21011, sometimes in a dose-dependent manner 12. As digoxin is frequently coadministered with P-gp inhibitors, we wanted to i) evaluate whether clinically relevant interactions are observed in a large group of ordinary digoxin patients and ii) investigate whether patients taking several P-gp inhibitors have additive elevations in S-digoxin levels compared with patients with one concomitantly prescribed P-gp inhibitor.

Rathore et al. (2003) 9 recently reported that the mortality rate was increased at S-digoxin levels above 1.5 nmol/L. Therefore, it is particularly important to be aware of factors that influence S-digoxin levels. We consider the magnitudes of the differences seen in S-digoxin in this study, 20–60% increases, to be of clinical importance. The patients taking one or more P-gp inhibitor had S-digoxin levels above 1.5 nmol/L, while patients without P-gp inhibitors were below this limit.

Pharmacokinetic interactions with digoxin can arise from mechanisms other than P-gp, for example, changes in renal function, changes in gut motility or pH, disturbances of digoxin-metabolizing intestinal bacteria or possibly from interactions with other transport proteins, such as members of the solute carrier family (SLC) 13. P-gp seems, however, to be a major determinant for digoxin pharmacokinetics.

Drugs with structures similar to digoxin can interfere with digoxin immunoassays 14. Of the concomitant drugs taken by the patients in this study, spironolactone and its metabolites have been reported to interfere with the digoxin readings 15. That spironolactone can interfere with digoxin immunoassays has been known for 30 years 16, but until recently little information about this effect has been available for newer digoxin assays. In a 1999 report by Steimer et al. 17, a case of digoxin toxicity resulted from falsely low values using the MEIA II assay for digoxin (AxSYM^®; Abbott). Canrenone and spironolactone were identified as the major interfering substances. In a subsequent study, Steimer et al. (2002) 15 examined nine digoxin assays including the TDx^® used in our study. False-negative results were attributable to spironolactone, canrenone and other steroids in several newer digoxin assays. In contrast, falsely increased digoxin concentrations could be detected in the TDx assay^®, although these were very small except in the absence of digoxin and at high concentrations of the interfering substance. In updated product information for the TDx assay^® released by Abbott Scandinavia AB 18, the results of a careful study of the analytical interference from spironolactone, canrenone and other steroids confirmed the results of Steimer et al. 15. Spironolactone and canrenone, at concentrations estimated to be the maximal blood concentrations found in patients treated with these drugs, were shown to increase the digoxin concentration by 4% and 15%, respectively. Spironolactone metabolites at concentrations corresponding to a daily intake of 100 mg falsely increased the digoxin concentration by 7%.

It is important to note that the doses recommended for patients with heart failure are considerably lower than this (12.5–50 mg). The average intake in our study was 34 mg/day. Furthermore, our results cannot be due to assay interference because the association between serum digoxin concentrations and P-gp inhibitors remains statistically significant even when all patients on spironolactone are excluded from the study (1.46 ± 0.05 compared with 1.26 ± 0.04 nmol/L, P < 0.001, for patients with and without concomitant P-gp inhibitors, respectively).

Likely explanations for the more pronounced effect of Class I P-gp inhibitors on S-digoxin levels compared with Class II P-gp inhibitors are the inhibitory concentrations for a certain drug in relation to the concentrations achieved in clinical use. As the drugs have been evaluated for P-gp inhibitory effect using several different in vitro methods, it was not proper to perform a comparison of the K_i or IC₅₀ values from the literature. A majority of the Class I inhibitors are given at higher doses than Class II inhibitors (the range of the lowest recommended doses is 10–200 mg for Class I vs. 0.25–60 mg for Class II), and the Class I inhibitors are often more potent, inhibiting digoxin transport by P-gp in vitro at lower concentrations. Other factors, such as time-point for the administration and physiochemical properties of the drug, might also contribute to the effect seen in vivo. Today, the in vitro data used to select the Class II drugs is not sufficient for the prediction of clinically relevant P-gp interactions in vivo. Before such interactions are fully understood, the Class II drugs should be regarded as potential mediators of drug-drug interactions when coadministered with digoxin or other P-gp substrates.

P-gp has a broad substrate specificity and, unfortunately, it is not possible to state that a particular group of drugs, for example, calcium channel blockers or HMG-coenzyme A inhibitors, are P-gp inhibitors with potential clinical consequences. For instance, verapamil is a P-gp inhibitor demonstrating clinical effects on digoxin kinetics, whereas diltiazem is not 19. Similarly, the HMG-coenzyme A inhibitor pravastatin is not an in vitro P-gp inhibitor 20, in contrast to atorvastatin, which is an in vitro P-gp inhibitor that also demonstrates in vivo effects on P-gp 11. Any investigation of P-gp inhibitory effects and possible clinical consequences should, therefore, be made for each single drug entity.

In this report we show that coadministration of P-gp inhibitors with digoxin is associated with significant elevations in S-digoxin levels in an ordinary group of digoxin patients. To avoid exposing patients to excessive digoxin levels, prescribing clinicians should consider potential P-gp interactions. Particular notice should be taken when more than one P-gp inhibitor is coadministered with digoxin, as administration of more than one P-gp inhibitor is associated with additive elevations in S-digoxin levels.

None declared.

GE participated in the collection of the patient material, the computer analysis of the data, the classification of P-gp-inhibitors and in the writing of the manuscript. PH participated in the collection of the patient material, the computer analysis of the data and in the writing of the manuscript. PA participated in the analysis of the data and in the writing of the manuscript. KM participated in the in the computer analysis of the data. HM conceived the study and participated in its design and in the writing of the manuscript.

All authors read and approved the final manuscript.