Prodrugs pp 1395-1402 | Cite as

Case Study: Ximelagatran: A Double Prodrug of Melagatran

  • Olafur S. Gudmundsson
Part of the Biotechnology: Pharmaceutical Aspects book series (PHARMASP, volume V)


Ximelagatran was designed to increase the bioavailability of melagatran, a potent thrombin inhibitor, by eliminating charges and thus increasing the lipophilicity of the molecule. Melagatran, like most other thrombin inhibitors, contains a strongly basic benzamidine group with a pKa of 11.5 that is protonated at the pH of the intestinal tract and hinders intestinal absorption. Furthermore, melagatran also contains an acidic carboxylic group with a pKa of 2.0, which is ionized at physiological pH. Melagatran also contains a secondary amine with a pKa of 7.0. The effect of the charges on the oral absorption of melagatran was observed when the compound was initially dosed orally and a low and variable bioavailability of 3–7% was observed (Gustafsson et al., 2001).


Nitric Oxide Ethyl Ester Secondary Amine Oral Absorption Direct Thrombin Inhibitor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Antonsson KT, Bylund RE, Gustafsson ND, and Nilsson NO. I. Trypsin-like Protease-inhibiting Peptide Derivatives, their Synthesis and Therapeutic Use. 1994; Wo 9429336. (Astra Aktiebolag, Swed.)Google Scholar
  2. Antonsson T, Gustafsson D, Hoffmann K-J, Nystrom J-E, Sorensen H, and Sellen M. Preparation of Peptide Derivatives as Prodrugs of Thrombin Inhibitors. 1997; Wo 9723499. (Astra Aktiebolag, Swed.)Google Scholar
  3. Bredberg, E., Andersson, T. B., Frison, L., Thuresson, A., Johansson, S., Eriksson-Lepkowska, M., Larsson, M. and Eriksson, U. G. Ximelagatran, An Oral Direct Thrombin Inhibitor, Has a Low Potential for Cytochrome P450-mediated Drug-Drug Interactions. Clin Pharmacokinet 2003; 42:765–777PubMedCrossRefGoogle Scholar
  4. Clement B. Reduction of N-hydroxylated Compounds: Amidoximes (Nhydroxyamidines) as Pro-drugs of Amidines. Drug Metab Rev 2002; 34:565–579PubMedCrossRefGoogle Scholar
  5. Clement B, and Lopian K. Characterization of in vitro Biotransformation of New, Orally Active, Direct Thrombin Inhibitor Ximelagatran, an Amidoxime and Ester Prodrug. Drug Metab Disp 2003; 31:645–651CrossRefGoogle Scholar
  6. Clement B, Christiansen K, and Girreser U. Phase 2 Metabolites of Nhydroxylated Amidines (Amidoximes): Synthesis, in vitro Formation by Pig Hepatocytes, and Mutagenicity Testing. Chem Res Toxicol 2001; 14:319–326PubMedCrossRefGoogle Scholar
  7. Eriksson UG, Bredberg U, Hoffmann K-J, Thuresson A, Gabrielsson M, Ericsson H, Ahnoff M, Gislen K, Fager G, and Gustafsson D. Absorption, Distribution, Metabolism, and Excretion of Ximelagatran, An Oral Direct Thrombin Inhibitor, in Rats, Dogs, and Humans. Drug Metab Disp 2003a; 31:294–305CrossRefGoogle Scholar
  8. Eriksson UG, Bredberg U, Gislen K, Johansson LC, Frison L, Ahnoff M, and Gustafsson D. Pharmacokinetics and Pharmacodynamics of Ximelagatran, a Novel Oral Direct Thrombin Inhibitor, in Young Healthy Male Subjects. Eur J Clin Pharmacol 2003b; 59:35–43PubMedGoogle Scholar
  9. Gustafsson D. Oral Direct Thrombin Inhibitors in Clinical Development. J Intern Med 2003; 254:322–334PubMedCrossRefGoogle Scholar
  10. Gustafsson D, and Elg M. The Pharmacodynamics and Pharmacokinetics of the Oral Direct Thrombin Inhibitor Ximelagatran and Its Active Metabolite Melagatran: A Mini-review. Thromb Res 2003; 109;Suppl. 1:S9–S15PubMedCrossRefGoogle Scholar
  11. Gustafsson D, Nystrom J-E, Carlsson S, Bredberg U, Eriksson U, Gyzander E, Elg M, Antonsson T, Hoffmann K-J, and Ungell A-L. The Direct Thrombin Inhibitor Melagatran and Its Oral Prodrug H 376/95: Intestinal Absorption Properties, Biochemical and Pharmacodynamic Effects. Thromb Res 2001; 101:171–181PubMedCrossRefGoogle Scholar
  12. Mansuy D, Boucher JL, and Clement B. On the Mechanism of Nitric Oxide Formation upon Oxidative Cleavage of C=N(OH) Bonds by NO-synthases And Cytochromes P450. Biochimie 1995; 77:661–667PubMedCrossRefGoogle Scholar
  13. Sarich TC, Johansson S, Schuetzer K-M, Wall U, Kessler E, Teng R, and Eriksson UG. The Pharmacokinetics and Pharmacodynamics of Ximelagatran, An Oral Direct Thrombin Inhibitor, Are Unaffected by a Single Dose of Alcohol. J Clin Pharmacol 2004; 44:388–393PubMedCrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2007

Authors and Affiliations

  • Olafur S. Gudmundsson
    • 1
  1. 1.Discovery PharmaceuticsBristol Myers Squibb Co.Princeton

Personalised recommendations