Contribution of increased oral bioavailability and reduced nonglomerular renal clearance of digoxin to the digoxin–clarithromycin interaction

Abstract

Aims A clinically important interaction between the cardiac glycoside digoxin and the antibiotic clarithromycin has been suggested in earlier reports. The aim of this study was to investigate the extent of the interaction and the relative contribution of different mechanisms. Methods In a randomized, placebo-controlled, double-blind cross-over design single oral doses of 0.75 mg digoxin with oral coadministration of placebo or 250 mg clarithromycin twice daily for 3 days were administered to 12 healthy men. Additionally, three of the subjects received single intravenous doses of 0.01 mg kg -1 digoxin with oral placebo or clarithromycin. Digoxin plasma and urine concentrations were determined by a highly sensitive radioimmunoassay. Results Oral coadministration of clarithromycin resulted in a 1.7-fold increase of the area under the digoxin plasma concentration-time curve [mean AUC(0,24) ± SD 23 ± 5.2 vs. 14 ± 2.9 m g L -1 h; 95% confidence interval (CI) on the difference 7.0, 12; P = 0.002] and in a reduction of the nonglomerular renal clearance of digoxin [mean Cl Rng (0, 24) ± SD 34 ± 39 vs. 57 ± 41 mL min -1 ; 95% CI on the difference 7.2, 45; P = 0.03]. The ratios of mean digoxin plasma concentrations with and without clarithromycin were highest during the absorption period of clarithromycin. After intravenous administration digoxin AUC(0,24) increased only 1.2-fold during coadministration of clarithromycin. Conclusions Increased oral bioavailability and reduced nonglomerular renal clearance of digoxin both contribute to the interaction between digoxin and clarithromycin, probably due to inhibition of intestinal and renal P-glycoprotein.

Effect of Goldenseal (Hydrastis canadensis) and Kava Kava (Piper methysticum) Supplementation on Digoxin Pharmacokinetics in Humans

“…Area under the plasma concentration time curves from 0 to 24 h [AUC (0 -24) ] and 0 to 3 h [AUC (0 -3) ] were determined by use of the trapezoidal rule. Rifampin, clarithromycin, and other P-gp modulators have significant effects on digoxin pharmacokinetics during the absorption phase (Greiner et al, 1999;Rengelshausen et al, 2003), which was the reason for evaluating AUC (0 -3) . The terminal elimination rate constant (k e ) was calculated using the slope of the log-linear regression of the terminal elimination phase.…”

“…In addition, we compare supplement effects with those of rifampin, an inducer of P-gp expression (Greiner et al, 1999), and clarithromycin, an inhibitor of P-gp activity (Rengelshausen et al, 2003), as a means of gauging the clinical relevancy of supplement-mediated interactions.…”

The Influence of Macrolide Antibiotics on the Uptake of Organic Anions and Drugs Mediated by OATP1B1 and OATP1B3

“…By inhibition of P-glycoprotein function they increase drug absorption from the gut lumen and decrease biliary elimination and renal secretion of concomitantly administered drugs such as the cardiac glycoside digoxin (Rengelshausen et al, 2003). This in turn leads to increased drug concentrations and drug toxicity.…”

Pharmacokinetic Characterization of Transcellular Transport and Drug Interaction of Digoxin in Caco-2 Cell Monolayers

“…Some such as carvedilol interact with digoxin, 4) whereby the plasma digoxin concentration is increased when carvedilol and digoxin are orally administered, while carvedilol does not affect the digoxin concentration when digoxin is intravenously administered. 4) Erythromycin, 5) clarithromycin [5][6][7] and talinolol 8) also interact in a similar way with digoxin. Together, these observations suggest that the increased digoxin concentration is not due to a decrease in its renal excretion, but rather an increase in bioavailability, and that the increased bioavailability is probably a consequence of these compounds enhancing the intestinal digoxin absorption.…”