Effect of clarithromycin on renal excretion of digoxin: Interaction with P-glycoprotein*

Abstract

We present a digoxin-clarithromycin interaction in two patients in whom digoxin concentrations were unexpectedly increased. The ratio of renal digoxin clearance to creatinine clearance in one patient was lower during the concomitant administration of clarithromycin (0.64 and 0.73) than that after cessation of clarithromycin administration (1.30 +/- 0.20; mean +/- SD). Because P-glycoprotein could play an important role in the renal secretion of digoxin, we hypothesized that clarithromycin decreases renal digoxin excretion by inhibiting P-glycoprotein-mediated transport. Digoxin transport was evaluated with use of a kidney epithelial cell line, which expresses the human P-glycoprotein on the apical membrane by transfection with MDR1 complementary deoxyribonucleic acid. Clarithromycin inhibited the transcellular transport of digoxin from the basolateral to the apical side in a concentration-dependent manner and concomitantly increased the cellular accumulation of digoxin. These results suggest that clarithromycin may inhibit the P-glycoprotein-mediated tubular secretion of digoxin, and this interaction mechanism may contribute to an increase in the serum digoxin concentration.

Digitalis Toxicity: A Fading but Crucial Complication to Recognize

“…7,9,10 Interacting drugs that are used in a variety of cardiac disease states, including amiodarone, verapamil, quinidine, macrolides, itraconazole, and cyclosporine, have been demonstrated in in vitro studies to inhibit P-glycoprotein transport in renal tubular cells. [17][18][19][20][21] P-glycoprotein is a 170-kDa membrane efflux transport protein that is located in the liver, pancreas, kidney, colon, and jejunum. Its theoretical mechanism involves active transport of digoxin into the urine, which leads to decreased clearance in the presence of glycoprotein inhibitors.…”

Common single nucleotide polymorphisms of the MDR1 gene have no influence on its mRNA expression level of normal kidney cortex and renal cell carcinoma in Japanese nephrectomized patients

“…In addition, concomitant administration with various drugs, including cyclosporin A, calcium channel blockers, macrolide antibiotics, and azole antifungal drugs elevates serum concentration of digoxin, at least in part, via renal tubular Pgp (Rodin and Johnson 1988;Wakasugi et al 1998). Considering these pharmacokinetic significances of renal Pgp, the expression levels and activity of Pgp in the kidney would be a key factor for the optimal dosage regimen of digoxin.…”

Six‐month oral clarithromycin regimen is safe and active in extranodal marginal zone B‐cell lymphomas: final results of a single‐centre phase II trial

“…They enhance the antitumour activity of macrophages, natural killer-and CD8 cytotoxic T-cells, reduce neutrophil production of interleukin-8, and inhibit tumour necrosis factor-a and vascular endothelial growth factor activity (Aoki et al, 2005). Clarithromycin is a substrate of P-glycoprotein, induces apoptotic changes in tumour cells and exhibits antitumour activity in different murine cancer models (Wakasugi et al, 1998;Hamada et al, 2000). These preclinical data constitute the rationale for prospective clinical trials addressing the antineoplastic activity of macrolides.…”