Influence of Erythromycin on the Pharmacokinetics of Ximelagatran May Involve Inhibition of P-Glycoprotein-Mediated Excretion

Abstract

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 Madin-Darby canine kidney-human multidrug resistance-1 cell preparations and on biliary excretion of melagatran in rats were studied. In healthy volunteers (seven males and nine females; mean age 24 years) receiving a single dose of ximelagatran 36 mg on day 1, erythromycin 500 mg t.i.d. on days 2 to 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 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.Ximelagatran is an oral direct thrombin inhibitor (oral DTI) which is available for the prevention of venous thromboembolic events in patients undergoing elective hip or knee replacement surgery and is being developed for the treatment of venous thromboembolic events, stroke prevention in patients with atrial fibrillation, and the secondary prevention of cardiovascular events after myocardial infarction (Bergsrud and Gandhi,

Intestinal and Hepatobiliary Transport of Ximelagatran and Its Metabolites in Pigs

“…ximelagatran administration . The formation of OH-melagatran and melagatran during passage through Caco-2 cell monolayers can be explained by the presence of hCE-1 in these cells (Imai et al, 2005;Eriksson et al, 2006). In pigs, the intestinal and liver CES isoforms are close to identical, exhibiting 77 and 76% sequence identity with hCE-1, respectively, and 47 and 46% sequence identity with hCE-2 (Musidlowska- Persson and Bornscheuer, 2003).…”

“…ximelagatran administration reflected in the bile as a result of active uptake of ethylmelagatran at the sinusoidal membrane. Transport studies in Caco-2 cells and P-gptransfected Madine-Darby canine kidney cells have indicated that ximelagatran is a substrate for P-gp (Eriksson et al, 2006). It has also been speculated that melagatran and OH-melagatran are transported by efflux transporters expressed at the apical membrane of the Caco-2 cells because these compounds were formed during the passage of ximelagatran through the Caco-2 monolayer and were preferentially excreted in the apical chamber (Eriksson et al, 2006).…”

“…Transport studies in Caco-2 cells and P-gptransfected Madine-Darby canine kidney cells have indicated that ximelagatran is a substrate for P-gp (Eriksson et al, 2006). It has also been speculated that melagatran and OH-melagatran are transported by efflux transporters expressed at the apical membrane of the Caco-2 cells because these compounds were formed during the passage of ximelagatran through the Caco-2 monolayer and were preferentially excreted in the apical chamber (Eriksson et al, 2006). Our study also supports the involvement of transport proteins in the hepatobiliary transport of melagatran; the melagatran concentration in bile was 100-fold greater than that in plasma, and FIG.…”

“…However, despite this, erythromycin increased the plasma concentrations of OH-melagatran, ethylmelagatran, and melagatran following concomitant administration with ximelagatran in healthy subjects (Eriksson et al, 2006). Data from cell culture and rat biliary excretion models suggested that the interaction was caused by erythromycin inhibiting the biliary excretion of melagatran (Eriksson et al, 2006). In this study, a pig model that simultaneously enables bile collection, intestinal perfusion, and plasma sampling from the portal vein (VP), hepatic vein (VH), and femoral vein (VF) was used to better understand the pharmacokinetics of ximelagatran and its metabolites, and the interaction with erythromycin.…”

“…In vitro and in vivo investigations have shown that neither ximelagatran nor its metabolites are substrates or inhibitors of any major cytochrome P450 isoenzymes . However, despite this, erythromycin increased the plasma concentrations of OH-melagatran, ethylmelagatran, and melagatran following concomitant administration with ximelagatran in healthy subjects (Eriksson et al, 2006). Data from cell culture and rat biliary excretion models suggested that the interaction was caused by erythromycin inhibiting the biliary excretion of melagatran (Eriksson et al, 2006).…”