Absorption, Distribution, Metabolism, and Excretion of Ximelagatran, an Oral Direct Thrombin Inhibitor, in Rats, Dogs, and Humans

Abstract

ABSTRACT: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.

The Multiple Depletion Curves Method Provides Accurate Estimates of Intrinsic Clearance (CLint), Maximum Velocity of the Metabolic Reaction (Vmax), and Michaelis Constant (Km): Accuracy and Robustness Evaluated through Experimental Data and Monte Carlo Simulations

“…Ideally, CL int , V max , and K m should also cover a wide range. The following seven substrates were selected, and the corresponding metabolites were used for determination of V max and K m by the traditional IFRMM: BRES O-dealkylation to RES mediated by CYP1A2 and CYP2B1 (Kobayashi et al, 2002); DFN 4-hydroxylation to 4DFN mediated by CYP2C6 (Kobayashi et al, 2002); DFN 5-hydroxylation to 5-OH-diclofenac (5DFN) mediated by multiple cytochrome P450s (Tang et al, 1999); DXM O-demethylation to DXO mediated by CYP2D2 (Kobayashi et al, 2002); ERES O-deethylation to RES mediated by CYP1A2 and CYP2C6 (Kobayashi et al, 2002); EMEL ester hydrolysis to MEL (specific enzymatic pathway unidentified) (Eriksson et al, 2003); FLU 2-hydroxylation to 2FLU mainly mediated by CYP1A2 (Berson et al, 1993;Fau et al, 1994); and NMEL reduction to MEL (specific enzymatic pathway unidentified) (Eriksson et al, 2003). The reactions are displayed in Fig.…”

The use of biopharmaceutic classification of drugs in drug discovery and development: current status and future extension

“…Melagatran, a direct thrombin inhibitor, is a recent and illustrative example of how intestinal permeability is increased and the development potential of a drug is increased (Eriksson et al 2002(Eriksson et al , 2003. It is produced by adding protecting chemical groups to its prodrug ximelagatran (H376/95), which results in greater BA and less interindividual variability in the pharmacokinetics of melagatran.…”

Amidoxime Reductase System Containing Cytochrome b5 Type B (CYB5B) and MOSC2 Is of Importance for Lipid Synthesis in Adipocyte Mitochondria

“…Instead, prodrugs have been developed by N-hydroxylation of these amidine groups, converting them into amidoximes to improve their oral bioavailability as exemplified by the direct thrombin inhibitor ximelagatran (1,2), its follow-up compound AZD0837 (3), and a platelet inhibitor sibrafidan (4). Once these prodrugs are absorbed into the body, they are reduced back to their bioactive amidines by a reductive enzyme system believed to be composed of cytochrome b 5 (CYB5), 3 cytochrome b 5 reductase (CYB5R), and a third unknown component and is associated with both the microsomal fraction (5) as well as the mitochondrial fraction (6,7).…”