Therapeutic Implications of the Unusually Long Half-Life of (E)-5-(2-BRO-Movinyl)Uracil (BVUra) in Vivo

The in vivo degradation of those pyrimidine analogues that are endowed with antiviral or antitumor activity, may obviously affect the therapeutic usefulness of these drugs. Indeed, pyrimidine nucleosides or bases are generally subjected to rapid catabolism leading to products devoid of therapeutic activity. Thus, several 5-substituted-2′-deoxyuridine (dUrd) analogues are substrates for pyrimidine nucleoside phosphorylases (PNPases) which degrade them to their corresponding bases (1,2). Likewise, several 5-substituted uracil (Ura) analogues, and in particular 5-halogenated Ura analogues, are subject to a reductive catabolic pathway with, as the first step, the reduction of the 5:6 double bond of the pyrimidine ring by a dihydropyrimidine (H2Thy) dehydrogenase (3). Advantage can be taken from the long half-life of BVUra in the plasma, (i) to regenerate the potent antiviral drug (E)-5-(2-bromovinyl)-2′-deoxyuridine (BVdUrd) (4) from BVUra by a pentosyl transfer and (ii) to enhance the therapeutic activity of 5-fluoro-Ura (FUra) by inhibition of its degradation by BVUra. The present study is focussed on the pharmacokinetics of BVUra and BVdUrd in rat plasma and the modalities of the (re)generation of BVdUrd from BVUra.