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Vol. 31, Issue 3, 294-305, March 2003
AstraZeneca R&D Mölndal, Mölndal, Sweden
The absorption, metabolism, and excretion of the oral direct
thrombin inhibitor, ximelagatran, and its active form, melagatran, were
separately investigated in rats, dogs, and healthy male human subjects
after administration of oral and intravenous (i.v.) single doses.
Ximelagatran was rapidly absorbed and metabolized following oral
administration, with melagatran as the predominant compound in plasma.
Two intermediates (ethyl-melagatran and OH-melagatran) that were
subsequently metabolized to melagatran were also identified in plasma
and were rapidly eliminated. Melagatran given i.v. had relatively low
plasma clearance, small volume of distribution, and short elimination
half-life. The oral absorption of melagatran was low and highly
variable. It was primarily renally cleared, and the renal clearance
agreed well with the glomerular filtration rate. Ximelagatran was
extensively metabolized, and only trace amounts were renally excreted.
Melagatran was the major compound in urine and feces after
administration of ximelagatran. Appreciable quantities of
ethyl-melagatran were also recovered in rat, dog, and human feces after
oral administration, suggesting reduction of the hydroxyamidine group
of ximelagatran in the gastrointestinal tract, as demonstrated when
ximelagatran was incubated with feces homogenate. Polar metabolites in
urine and feces (all species) accounted for a relatively small fraction
of the dose. The bioavailability of melagatran following oral
administration of ximelagatran was 5 to 10% in rats, 10 to 50% in
dogs, and about 20% in humans, with low between-subject variation. The
fraction of ximelagatran absorbed was at least 40 to 70% in all
species. First-pass metabolism of ximelagatran with subsequent biliary
excretion of the formed metabolites account for the lower
bioavailability of melagatran.
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