Absorption, distribution, metabolism, and excretion of ximelagatran, an oral direct thrombin inhibitor, in rats, dogs, and humans

Drug Metabolism and Disposition

Volumn 31, Issue 3, 2003, Pages 294-305

  Eriksson, Ulf G ^a   Bredberg, Ulf ^a   Hoffmann, Kurt Jürgen ^a   Thuresson, Anneli ^a   Gabrielsson, Margareth ^a   Ericsson, Hans ^a   Ahnoff, Martin ^a   Gislén, Kristina ^a   Fager, Gunnar ^a   Gustafsson, David ^a  

^a ASTRAZENECA R AND D   (Sweden)

Author keywords

[No Author keywords available]

Indexed keywords

DRUG METABOLITE; MELAGATRAN; THROMBIN INHIBITOR; XIMELAGATRAN;

ADULT; ANIMAL EXPERIMENT; ARTICLE; DOG; DRUG ABSORPTION; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG CLEARANCE; DRUG DISTRIBUTION; DRUG EXCRETION; DRUG HALF LIFE; DRUG METABOLISM; DRUG STRUCTURE; DRUG URINE LEVEL; FEMALE; FIRST PASS EFFECT; GLOMERULUS FILTRATION RATE; HUMAN; KIDNEY CLEARANCE; MALE; NONHUMAN; NORMAL HUMAN; PLASMA CLEARANCE; PRIORITY JOURNAL; RAT;

ABSORPTION; ADMINISTRATION, ORAL; ADULT; ANIMALS; AREA UNDER CURVE; AZETIDINES; BENZYLAMINES; DOGS; DOSE-RESPONSE RELATIONSHIP, DRUG; FEMALE; HUMANS; MALE; MIDDLE AGED; RATS; RATS, SPRAGUE-DAWLEY; THROMBIN; TISSUE DISTRIBUTION;

ANIMALIA; CANIS FAMILIARIS; GLOMERULUS;

EID: 0037372498     PISSN: 00909556     EISSN: None     Source Type: Journal    
DOI: 10.1124/dmd.31.3.294     Document Type: Article

References (25)

1. Anonymous (1993) Biverkningsnytt. Rekordantal rapporter 1992. Läkartidningen 90:2533-2534.
2. Antonsson T, Bylund R, Gustafsson D, and Nilsson I (1994) inventors, Trypsin-like protease-inhibiting peptide derivatives, their synthesis and therapeutic use. PTC patent application WO 94/29336.
3. Antonsson T, Gustafsson D, Hoffmann K-J, Nyström J-E, Sörensen H, and Sellén M (1997) inventors, Preparation of peptide derivatives as prodrug of thrombin inhibitors. PTC patent application WO 97/23499.
4. Chiou WL, Jeong HY, Chung SM, and Wu TC (2000) Evaluation of using dog as an animal model to study the fraction of oral dose absorbed of 43 drugs in humans. Pharm Res (NY) 17:135-140.
5. Clement B (1998) inventor, Pharmaceutical preparation. Patent application US 5,786,383.
6. Davies B and Morris T (1993) Physiological parameters in laboratory animals and humans. Pharm Res (NY) 10:1093-1095.
7. Elg M, Gustafsson D, and Carlsson S (1999) Antithrombotic effects and bleeding time of thrombin inhibitors and warfarin in the rat. Thromb Res 94:187-197.
8. Elg M, Gustafsson D, and Deinum J (1997) The importance of enzyme inhibition kinetics for the effect of thrombin inhibitors in a rat model of arterial thrombosis. Thromb Haemost 78:1286-1292.
9. Eriksson BI, Arfwidsson A-C, Frison L, Eriksson UG, Bylock A, Kälebo P, Fager G, and Gustafsson D (2002a) A dose-ranging study of the oral direct thrombin inhibitor, ximelagatran and its subcutaneous form, melagatran, compared with dalteparin in the prophylaxis of thromboembolism after hip or knee replacement: METHRO I. MElagatran for THRombin inhibition in Orthopaedic surgery. Thromb Haemost 87:231-237.
10. Eriksson BI, Bergqvist D, Kälebo P, Dahl OE, Lindbratt S, Bylock A, Frison L, Eriksson UG, Welin L, and Gustafsson D (2002b) The oral direct thrombin inhibitor, ximelagatran and its active form, melagatran, in ascending doses compared with dalteparin for prevention of venous thromboembolism after total hip or total knee replacement: The METHRO II study. Lancet 360:1441-1447.
11. Eriksson BI, Carlsson S, Halvarsson M, Risberg B, and Mattsson C (1997) Antithrombotic effect of two low molecular weight thrombin inhibitors and a low molecular weight heparin in a caval vein thrombosis model in the rat. Thromb Haemost 78:1404-1407.
12. Eriksson BI, Ogren M, Eriksson UG, Kälebo P, Ahnfelt L, Björkström S, Sjöstedt Å, Folestad A, Arfwidsson A-C, Elvander CS, and Frison L (2002c) Prophylaxis of venous thromboembolism with subcutaneous melagatran in total hip or total knee replacement: results from phase II studies. Thromb Res 105:371-378.
13. Eriksson H, Eriksson UG, Frison L, Hansson PO, Held P, Holmström M, Hägg A, Jonsson T, Lapidus L, Leijd B, Stockelberg D, Säfwenberg U, and Taghavi A (1999a) Pharmacokinetics and pharmacodynamics of melagatran, a novel synthetic LMW thrombin inhibitor, in patients with acute DVT. Thromb Haemost 81:358-363.
14. Eriksson H, Wåhlander K, Gustafsson D, Welin L, Frison L, and Schulman S. (2003) A randomised, controlled, dose-guiding study of the oral direct thrombin inhibitor ximelagatran compared with standard therapy for the treatment of acute deep vein thrombosis: THRIVE I. J Thromb Haemost 1:1-7.
15. Eriksson UG, Johansson L, Frison F, Bredberg U, and Gustafsson D (1999b) Single and repeated oral dosing of H 376/95, a prodrug of the direct thrombin inhibitor melagatran, to young healthy subjects. Blood 94:26a.
16. Gustafsson D, Antonsson T, Bylund R, Eriksson U, Gyzander E, Nilsson I, Elg M, Mattson C, Deinum J, Pehrsson S, et al. (1998) Effects of melagatran, a new low-molecular-weight thrombin inhibitor, on thrombin and fibrinolytic enzymes. Thromb Haemost 79:110-118.
17. Gustafsson D, Nyström J-E, Carlsson S, Bredberg U, Eriksson U, Gyzander E, Elg M, Antonsson T, Hoffmann K-J, Ungell A-L, et al. (2001) The direct thrombin inhibitor melagatran and its oral prodrug H 376/95: intestinal absorption properties, biochemical and pharmacodynamic effects. Thromb Res 101:171-181.
18. Heit JA, Colwell CW, Francis CW, Ginsberg JS, Berkowitz SD, Whipple I, and Peters G (2001) Comparison of the oral direct thrombin inhibitor ximelagatran with enoxaparin as prophylaxis against venous thromboembolism after total knee replacement. Arch Intern Med 161:2215-2221.
19. Hirsh J, Dalen JE, Anderson DR, Poller L, Bussey H, Ansell J, and Deykin D (2001) Oral anticoagulants. Mechanism of action, clinical effectiveness and optimal therapeutic range. Chest 119:8S-21S.
20. Holm G, Hanssen K, and Svensson L (1985) Use of dodecyl sulfate as an esterase inhibitor before gas-chromatographic determination of labile β-adrenoceptor blocking drugs. Clin Chem 31:868-870.
21. Hull RD and Pineo GF (1995) Treatment of venous thrornboembolism with low-molecular weight heparin. J Thromb Thrombolysis 1:279-284.
22. Larsson M, Ahnoff M, Abrahamsson A, Logren U, Fakt C, Ohrman I, and Persson B-A (2003) Determination of ximelagatran, an oral direct thrombin inhibitor, its active metabolite melagatran, and the intermediate metabolites, in biological samples by liquid chromatographymass spectrometry. J Chromatogr B 783:335-347.
23. Larsson M, Logren U, Ahnoff M, Lindmark B, Abrahamsson P, Svennberg H, and Persson B-A (2002) Determination of melagatran, a novel, direct thrombin inhibitor, in human plasma and urine by liquid chromatography-mass spectrometry. J Chromatogr B 766:47-55.
24. Mattsson C, Björkman JA, and Ulvinge JC (1997) Melagatran, hirudin and heparin as adjuncts to tissue-type plasminogen activator in the canine model of coronary artery thrombolysis. Fibrinolysis Proteolysis 11:121-128.
25. Metha J, Chen L, Nichols WW, Mattsson C, Gustafsson D, and Saldeen GP (1998) Melagatran, an oral active site inhibitor of thrombin, prevents or delays formation of electrically induced occlusive thrombus in the canine coronary artery. J Cardiovasc Pharmacol 31:345-351.