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Association between the number of coadministered P-glycoprotein inhibitors and serum digoxin levels in patients on therapeutic drug monitoring.

Englund G, Hallberg P, Artursson P, Michaëlsson K, Melhus H - BMC Med (2004)

Bottom Line: The question of whether several P-gp inhibitors may have additive effects has not yet been addressed.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).As coadministration of digoxin and P-gp inhibitors is common, it is important to increase awareness about P-gp interactions among prescribing clinicians.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medical Sciences, Uppsala University, Uppsala, Sweden. gunilla.englund@farmaci.uu.se <gunilla.englund@farmaci.uu.se>

ABSTRACT

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.

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The association between S-digoxin levels and the number of prescribed P-gp inhibitors (A) Adjusted* S-digoxin means for the patients without ('0') (N = 328, S-digoxin mean ± SE 1.26 ± 0.04 nmol/L) or with ('≥ 1'), P-gp inhibitors (N = 290, S-digoxin mean ± SE 1.55 ± 0.04 nmol/L). (B) Adjusted* S-digoxin means for patients taking zero, one, two or three P-gp inhibitors. The number of patients were 328, 204, 78 and eight, respectively. The S-digoxin means ± SE (nmol/L) were 1.26 ± 0.04, 1.51 ± 0.05, 1.59 ± 0.08 and 2.00 ± 0.25. *Adjusted for age, sex, digoxin dose and total number of prescribed drugs.
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Figure 1: The association between S-digoxin levels and the number of prescribed P-gp inhibitors (A) Adjusted* S-digoxin means for the patients without ('0') (N = 328, S-digoxin mean ± SE 1.26 ± 0.04 nmol/L) or with ('≥ 1'), P-gp inhibitors (N = 290, S-digoxin mean ± SE 1.55 ± 0.04 nmol/L). (B) Adjusted* S-digoxin means for patients taking zero, one, two or three P-gp inhibitors. The number of patients were 328, 204, 78 and eight, respectively. The S-digoxin means ± SE (nmol/L) were 1.26 ± 0.04, 1.51 ± 0.05, 1.59 ± 0.08 and 2.00 ± 0.25. *Adjusted for age, sex, digoxin dose and total number of prescribed drugs.

Mentions: Overall, patients with concomitant P-gp inhibitors had higher S-digoxin levels than patients without: 1.55 ± 0.04 compared with 1.26 ± 0.04 nmol/L, P < 0.001 (the results differed in the third decimal between the univariate and multivariate analyses [Figure 1A]). Subclass analysis of the 542 patients for whom p-creatinine was available did not alter these results. An increasing number of P-gp inhibitors was associated with stepwise elevations in S-digoxin levels (Figure 1B).


Association between the number of coadministered P-glycoprotein inhibitors and serum digoxin levels in patients on therapeutic drug monitoring.

Englund G, Hallberg P, Artursson P, Michaëlsson K, Melhus H - BMC Med (2004)

The association between S-digoxin levels and the number of prescribed P-gp inhibitors (A) Adjusted* S-digoxin means for the patients without ('0') (N = 328, S-digoxin mean ± SE 1.26 ± 0.04 nmol/L) or with ('≥ 1'), P-gp inhibitors (N = 290, S-digoxin mean ± SE 1.55 ± 0.04 nmol/L). (B) Adjusted* S-digoxin means for patients taking zero, one, two or three P-gp inhibitors. The number of patients were 328, 204, 78 and eight, respectively. The S-digoxin means ± SE (nmol/L) were 1.26 ± 0.04, 1.51 ± 0.05, 1.59 ± 0.08 and 2.00 ± 0.25. *Adjusted for age, sex, digoxin dose and total number of prescribed drugs.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC411066&req=5

Figure 1: The association between S-digoxin levels and the number of prescribed P-gp inhibitors (A) Adjusted* S-digoxin means for the patients without ('0') (N = 328, S-digoxin mean ± SE 1.26 ± 0.04 nmol/L) or with ('≥ 1'), P-gp inhibitors (N = 290, S-digoxin mean ± SE 1.55 ± 0.04 nmol/L). (B) Adjusted* S-digoxin means for patients taking zero, one, two or three P-gp inhibitors. The number of patients were 328, 204, 78 and eight, respectively. The S-digoxin means ± SE (nmol/L) were 1.26 ± 0.04, 1.51 ± 0.05, 1.59 ± 0.08 and 2.00 ± 0.25. *Adjusted for age, sex, digoxin dose and total number of prescribed drugs.
Mentions: Overall, patients with concomitant P-gp inhibitors had higher S-digoxin levels than patients without: 1.55 ± 0.04 compared with 1.26 ± 0.04 nmol/L, P < 0.001 (the results differed in the third decimal between the univariate and multivariate analyses [Figure 1A]). Subclass analysis of the 542 patients for whom p-creatinine was available did not alter these results. An increasing number of P-gp inhibitors was associated with stepwise elevations in S-digoxin levels (Figure 1B).

Bottom Line: The question of whether several P-gp inhibitors may have additive effects has not yet been addressed.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).As coadministration of digoxin and P-gp inhibitors is common, it is important to increase awareness about P-gp interactions among prescribing clinicians.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medical Sciences, Uppsala University, Uppsala, Sweden. gunilla.englund@farmaci.uu.se <gunilla.englund@farmaci.uu.se>

ABSTRACT

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.

Show MeSH