INFLUENCE OF ERYTHROMYCIN ON THE PHARMACOKINETICS OF XIMELAGATRAN MAY INVOLVE INHIBITION OF P-GLYCOPROTEIN-MEDIATED EXCRETION

• Published in: Drug metabolism and disposition Vol. 34; no. 5; pp. 775 - 782
• Main Authors: ERIKSSON, Ulf G, DORANI, Hassan, KARLSSON, Johan, FRITSCH, Holger, HOFFMANN, Kurt-Jürgen, OLSSON, Lis, SARICH, Troy C, WALL, Ulrika, SCHÜTZER, Kajs-Marie
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Pharmacology and Experimental Therapeutics 01.05.2006
• Subjects: Adult; Animals; Anti-Bacterial Agents - adverse effects; Anti-Bacterial Agents - pharmacology; Antimalarials - pharmacology; ATP-Binding Cassette, Sub-Family B, Member 1 - antagonists & inhibitors; ATP-Binding Cassette, Sub-Family B, Member 1 - physiology; Azetidines - adverse effects; Azetidines - pharmacokinetics; Benzylamines - adverse effects; Benzylamines - pharmacokinetics; Bile - metabolism; Biological and medical sciences; Biological Transport, Active; Caco-2 Cells; Calcium Channel Blockers - pharmacology; Cell Line; Dogs; Dose-Response Relationship, Drug; Drug Interactions; Erythromycin - adverse effects; Erythromycin - pharmacology; Female; Humans; In Vitro Techniques; Male; Medical sciences; Partial Thromboplastin Time; Pharmacology. Drug treatments; Quinidine - pharmacology; Rats; Rats, Sprague-Dawley; Verapamil - pharmacology; Excretion; Serine endopeptidases; Hemostatic; Enzyme; P Glycoprotein; Enzyme inhibitor; Thrombin; Erythromycin; Prodrug; Ximelagatran; Antithrombin; Macrolide; Peptidases; Antibiotic; Antithrombotic agent; Hydrolases; Inhibition; Antibacterial agent; Pharmacokinetics
• ISSN: 0090-9556; 1521-009X
• DOI: 10.1124/dmd.105.008607

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-over-expressing 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.