Effect of clarithromycin on renal excretion of digoxin: interaction with P-glycoprotein.
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.
Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Japan.
H
H
Wakasugi
I
I
Yano
T
T
Ito
T
T
Hashida
T
T
Futami
R
R
Nohara
S
S
Sasayama
K
K
Inui
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects* / Q000378:metabolism; D000889:Anti-Arrhythmia Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D017291:Clarithromycin / Q000493:pharmacokinetics / Q000494:pharmacology*; D004077:Digoxin / Q000493:pharmacokinetics* / Q000494:pharmacology; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D008875:Middle Aged
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000889:Anti-Arrhythmia Agents; D000900:Anti-Bacterial Agents; D004077:Digoxin; D017291:Clarithromycin