ORIGINAL ARTICLEThe Direct Thrombin Inhibitor Melagatran and Its Oral Prodrug H 376/95: Intestinal Absorption Properties, Biochemical and Pharmacodynamic Effects☆
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Material and Methods
The chemical name of melagatran is: (Glycine, N-[(1R)-2-[(2S)-2-[[[[4-(aminoiminomethyl)phenyl]methyl]amino]carbonyl]-1-azetidinyl]-1-cyclohexyl-2-oxoethyl]-). The chemical name of H 376/95 is: (Glycine, N-[(1R)-1-cyclohexyl-2-[(2S)-2-[[[[4-[amino(hydroxyimino)methyl]phenyl]methyl]amino]carbonyl]-1-azetidinyl]-2-oxoethyl]-, ethyl ester). Melagatran and H 376/95 were synthesised analogously to methods described previously [20], [21] by AstraZeneca. The low molecular weight heparin, dalteparin
Chemical Structures and Charges
The difference between melagatran and H 376/95 is designated by X and Y in Fig. 1. In melagatran (X=Y=H), there is a strong acid (X=H, carboxylic acid, pKa 2.0) and a strong base (Y=H, amidine, pKa 11.5). In addition, the secondary amine (designated by an *) has a pKa of 7.0, implying that 50% of the melagatran molecules will be positively charged at pH 7 at the secondary amine. Melagatran is a pure zwitter ion at a pH of 8–10 when the carboxylic acid and the amidinium charges neutralise each
Discussion
In this communication, we demonstrate that by converting melagatran into a prodrug, the oral absorption of the direct thrombin inhibitor melagatran is increased 2.7- to 5.5-fold, thereby providing a drug with the potential for oral use in a clinical setting. Since melagatran has a relatively high molecular mass compared to other drugs given by the oral route, the working hypothesis was that if ‘melagatran’ could become uncharged and more lipophilic, its bioavailability when given orally would
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2016, European Journal of Pharmaceutical SciencesCitation Excerpt :Increasing lipophilicity of compound/drug promotes membrane permeation and thus oral absorption. These examples include enalapril (angiotensin converting enzyme inhibitor) (Beaumont et al., 2003; Todd and Heel, 1986), pivampicillin (β-lactam antibiotic) (Ehrnebo et al., 1979; Jusko and Lewis, 1973), oseltamivir (anti-influenza) (Bardsley-Elliot and Noble, 1999; Doucette and Aoki, 2001; McClellan and Perry, 2001), adefovir dipivoxil (antiviral) (Dando and Plosker, 2003; Noble and Goa, 1999), tenofovir disoproxil (antiviral) (Chapman et al., 2003; Gallant and Deresinski, 2003; Shaw et al., 1997), famciclovir (antiviral) (Gudmundsson and Antman, 2007; Hodge et al., 1989; Simpson and Lyseng-Williamson, 2006), ximelagatran (anticoagulant) (Eriksson et al., 2003; Gustafsson et al., 2001), MGS0210 (glutamate receptor antagonist) (Nakamura et al., 2006; Yasuhara et al., 2006) etc. This illustrates how sometimes the dramatic lowering of solubility can be an advantage for enhancing drug delivery and thus oral bioavailability.
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Presented as an oral communication at the 16th International Congress on Thrombosis, Porto, Portugal, May 5–8, 2000.