title: Biliary excretion of ximelagatran and its metabolites and the influence of erythromycin following intraintestinal administration to healthy volunteers.
abstract: The biliary excretion of the oral thrombin inhibitor ximelagatran and its metabolites was investigated by using duodenal aspiration in healthy volunteers following intraintestinal dosing. In the first investigation, radiolabeled [(14)C]ximelagatran was administered, enabling quantification of the biliary excretion and identification of metabolites in the bile. In the second study, the effect of erythromycin on the biliary clearance of ximelagatran and its metabolites was investigated to clarify the reported ximelagatran-erythromycin interaction. Approximately 4% of the intraintestinal dose was excreted into bile with ximelagatran and its active form, melagatran, being the most abundant compounds. Four novel ximelagatran metabolites were identified in bile (<0.1% of dose). Erythromycin changed the pharmacokinetics of ximelagatran and its metabolites, with an elevated ximelagatran (78% increase), OH-melagatran (89% increase), and melagatran (86% increase) plasma exposure and higher peak plasma concentrations of the compounds being measured. In parallel, the biliary clearance was moderately reduced. The results suggest that inhibition of hepatobiliary transport is a likely mechanism for the interaction between erythromycin and ximelagatran. Furthermore, the study demonstrated the value of direct bile sampling in humans for the identification of primary biliary metabolites.
authors.affiliation: Department of Pharmacy, Uppsala University, Uppsala, Sweden.
authors.forename: Elin M
authors.initials: EM
authors.lastname: Matsson
authors.forename: Ulf G
authors.initials: UG
authors.lastname: Eriksson
authors.forename: Lars
authors.initials: L
authors.lastname: Knutson
authors.forename: Kurt-Jürgen
authors.initials: KJ
authors.lastname: Hoffmann
authors.forename: Ulrika
authors.initials: U
authors.lastname: Logren
authors.forename: Patrik
authors.initials: P
authors.lastname: Fridblom
authors.forename: Niclas
authors.initials: N
authors.lastname: Petri
authors.forename: Hans
authors.initials: H
authors.lastname: Lennernäs
mesh_terms: D000328:Adult; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000991:Antithrombins / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001384:Azetidines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001596:Benzylamines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001646:Bile / Q000378:metabolism*; D001711:Biotransformation; D018592:Cross-Over Studies; D004386:Duodenum / Q000378:metabolism; D004917:Erythromycin / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D006207:Half-Life; D006801:Humans; D007441:Intubation, Gastrointestinal; D008297:Male; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D013548:Sweden; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D000991:Antithrombins; D001384:Azetidines; D001596:Benzylamines; C426686:ximelagatran; D004917:Erythromycin