Elsevier

Thrombosis Research

Volume 101, Issue 3, 1 February 2001, Pages 171-181
Thrombosis Research

ORIGINAL ARTICLE
The Direct Thrombin Inhibitor Melagatran and Its Oral Prodrug H 376/95: Intestinal Absorption Properties, Biochemical and Pharmacodynamic Effects

https://doi.org/10.1016/S0049-3848(00)00399-6Get rights and content

Abstract

Suboptimal gastrointestinal absorption is a problem for many direct thrombin inhibitors. The studies presented herein describe the new oral direct thrombin inhibitor H 376/95, a prodrug with two protecting residues added to the direct thrombin inhibitor melagatran. Absorption properties in vitro: H 376/95 is uncharged at intestinal pH while melagatran is charged. H 376/95 is 170 times more lipophilic (octanol water partition coefficient) than melagatran. As a result, the permeability coefficient across cultured epithelial Caco-2 cells is 80 times higher for H 376/95 than for melagtran. Pharmacokinetic studies in healthy volunteers: H 376/95 is converted to melagatran in man. Oral bioavailability, measured as melagatran in plasma, is about 20% after oral administration of H 376/95, which is 2.7–5.5 times higher than after oral administration of melagatran. The variability in the area under the drug plasma concentration vs. time curve (AUC) is much smaller with oral H 376/95 (coefficient of variation 20%) than with oral melagatran (coefficient of variation 38%). Pharmacodynamic properties: H 376/95 is inactive towards human α-thrombin compared with melagatran [inhibition constant (Ki) ratio, 185 times], a potential advantage for patients with silent gastrointestinal bleeding. In an experimental thrombosis model in the rat, oral H 376/95 was more effective than the subcutaneous low molecular weight heparin dalteparin in preventing thrombosis. Conclusion: By the use of the prodrug principle, H 376/95 endows the direct thrombin inhibitor melagatran with pharmacokinetic properties required for oral administration without compromising the promising pharmacodynamic properties of melagatran.

Section snippets

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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    Presented as an oral communication at the 16th International Congress on Thrombosis, Porto, Portugal, May 5–8, 2000.

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