Received for publication December 6, 2005.
Revised January 26, 2006.
Accepted for publication January 30, 2006.

Influence of Erythromycin on the Pharmacokinetics of Ximelagatran May Involve Inhibition of P-glycoprotein-mediated Excretion

Abstract

A pharmacokinetic interaction between erythromycin and ximelagatran, an oral direct thrombin inhibitor, was demonstrated in this study in healthy volunteers. To investigate possible interaction mechanisms, the effects of erythromycin on active transport mediated by P-glycoprotein (P-gp) in vitro in Caco-2 and P-gp overexpressing MDCK-MDR1 cell preparations and on biliary excretion of melagatran in rats were studied. In healthy volunteers (7 males and 9 females; mean age 24 years) receiving a single dose of ximelagatran 36 mg on Day 1, erythromycin 500 mg TID on Days 2-5, and a single dose of ximelagatran 36 mg plus erythromycin 500 mg on Day 6, the least-squares mean estimates (90% confidence intervals) for the ratio of ximelagatran with erythromycin to ximelagatran given alone were 1.82 (1.64-2.01) for the area under the concentration-time curve and 1.74 (1.52-2.00) for the maximum plasma concentration of melagatran, the active form of ximelagatran. Neither the slope nor the intercept of the melagatran plasma concentration-effect relationship for activated partial thromboplastin time (APTT) statistically significantly differed as a function of whether or not erythromycin was administered with ximelagatran. Ximelagatran was well tolerated regardless of whether it was administered with erythromycin. Erythromycin inhibited P-gp-mediated transport of both ximelagatran and melagatran in vitro and decreased the biliary excretion of melagatran in the rat. These results indicate that the mechanism of the pharmacokinetic interaction between oral ximelagatran and erythromycin may involve inhibition of transport proteins, possibly P-gp, resulting in decreased melagatran biliary excretion and increased bioavailability of melagatran.

Key words: antibiotics, clinical pharmacokinetics, drug interactions, drug-drug interactions, human pharmacokinetics, p-glycoprotein, pharmacokinetics, transporters

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