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Nucleic Acids Research, 1984, Vol. 12, No. 4 2081-2110
© 1984

MOLECULAR BIOLOGY

Regeneration of the antivirel drug (E)-5-(2-bromovinyl)-2' -deoxyuridine in vivo

Claude Desgranges*,+, Gabriel Razaka*, Françoise Drouiller*, Henri Bricaud*, Piet Herdewijn+ and Erik De Clercq+

*unité 8 de Cardiologie de I'INSERM Avenue du Haut-Levèque, 33600 Pessac, France +Institute for Medical Research, Katholieke Universiteit Leuven Minderbroedersstraat 10, B-3000 Leuven, Belgium

Received January 5, 1984. Accepted January 23, 1984.

The highly potent and selective antiherpes drug BVdUrd ((E)-5-(2-bromo-vinyl)-2'-deoxyuridine) is cleared within 2–3 hours from the bloodstream upon intraperitoneal administration to rats. It is degraded to BVUra ((E)-5-(2-bromovinyl)uracil) and this inactive metabolite is cleared very slowly from the bloodstream so that 24 hours after the administration of BVdUrd, BVUra is still detectable in the plasma. This contrasts with several other 5-substituted uracils, i.e. 5-fluorouracil, 5-iodouracil, 5-trifluorothymine and thymine itaelf, which are, like their 2'-deoxyuridines counterparts FdUrd, IdUrd, F3dThd and dThd, cleared from the plasma within 2–3 hours. The injection of dThd or any of the other 5-substituted 2'-deoxyuridines at 3 hours after the injection of BVdUrd, that is at a time when BVdUrd has disappeared completely from the circulation, results in the re-apparition of BVdUrd in the plasma. Apparently, BVdUrd is regenerated from BVUra following the reaction catalyzed by pyrimidine nucleoside phosphorylases BVUJra + dThd -> BVdUrd + Thy. BVdUrd can even be generated de novo if dThd (or FdUrd, IdUrd or F3dThd) are administered 3 hours after a preceding injection of BVUra. These findings represent a unique example of the (re)generation of an active drug from its inactive metabolite in vivo.


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