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.

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New Plastoquinones Isolated from the Brown Alga, Sargassum micracanthum. -Theplastoquinones (I)-(III), isolated from the brown alga Sargassum micracanthum, exhibit significant antioxidant activities such as an inhibitory effect on lipid peroxidation and a radical-scavenging effect on DPPH. Some of them show cytotoxic activity. -(MORI, J.; IWASHIMA*, M.; WAKASUGI, H.; SAITO, H.; MATSUNAGA, T.; OGASAWARA, M.; TAKAHASHI, S.; SUZUKI, H.; HAYASHI, T.; Chem. Pharm. Bull. 53 (2005) 9, 1159-1163; Fac. Pharm. Sci., Toyama Med. Pharm. Univ., Toyama 930, Japan; Eng.) -M. Bohle 08-202

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Summary: Itraconazole is known to interact with digoxin, a substrate of P-glycoprotein, in clinical situa tions. In this study, the interactions of the azole antifungal agents, miconazole, fluconazole, ketoconazole as well as itraconazole, with P-glycoprotein were examined using a transfected kidney epithelial cell line, LLC GA5-COL150, which expresses human P-glycoprotein on the apical membrane.Itraconazole decreased the transcellular transport of digoxin from the basolateral to apical side in LLC GA5-COL150 cell monolayers, that was accompanied by increased cellular accumulation. The basolateral to-apical transcellular transport of digoxin in the host LLC-PK1 cell monolayers was not affected by itracona zole. Ketoconazole and fluconazole also significantly inhibited P-glycoprotein-mediated transport of digoxin, although miconazole was not effective. The inhibitory effects of itraconazole and ketoconazole on digoxin transport in LLC-GA5-COL150 monolayers were as strong as that of cyclosporin A, a typical P glycoprotein modulator, and neither quinidine nor cimetidine inhibited digoxin transport at the same concen tration (10,uM). In addition, the viability of LLC-GA5-COL150 cells against itraconazole was higher than that of LLC-PK1 cells, but viability against the other three azoles was similar to that of LLC-PK1 cells.In conclusion, ketoconazole and fluconazole as well as itraconazole inhibited the transport of digoxin via human P-glycoprotein, and itraconazole could be a substrate of P-glycoprotein.

These findings suggest that rat oatp2 rather than Pgp may be one of the interaction sites for digoxin and amiodarone in the liver.

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