THE EFFECT OF SORIVUDINE ON DIHYDROPYRIMIDINE DEHYDROGENASE-ACTIVITY IN PATIENTS WITH ACUTE HERPES-ZOSTER

Objective: Bromovinyl-uracil (BUV) is the principal metabolite of sori vudine, a potent anti-tester nucleoside. BUV binds to, and irreversibl y inhibits, the enzyme dihydropyrimidine dehydrogenase (DPD). The obje ctive of this study was to assess the time course of recovery of DPD a ctivity after oral administration of sorivudine in patients with herpe s tester and to correlate restoration of DPD activity and levels of ur acil with the elimination of sorivudine and its metabolite BUV from th e circulation. Methods: Sorivudine was given orally as 40 mg once-dail y doses for 10 consecutive days to a total of 19 patients with herpes tester. Serum sorivudine, BUV, and circulating uracil and DPD activity in peripheral blood mononuclear cells (PBMCs) were determined before, during, and after administration of sorivudine. Results: BVU was elim inated from the circulation within 7 days after the last sorivudine do se. DPD activity in PBMCs, which was completely suppressed in 18 of th e 19 subjects and markedly suppressed in the remaining subject during administration of sorivudine, recovered to baseline levels within 19 d ays after the last dose of sorivudine in all subjects and within 14 da ys in all but one of the subjects. The restoration of DPD activity was temporally associated with elimination of BUV from the circulation. T he elevated uracil concentrations produced by inhibition of DPD activi ty fell rapidly after cessation of sorivudine administration and also were temporally associated with elimination of BVU from the circulatio n. The time course of recovery of DPD activity in three patients with renal impairment was similar to that of the other subjects. Conclusion s: This study indicates that sorivudine therapy is associated with a p rofound depression of DPD activity. Recovery of DPD activity occurred within 4 weeks of the completion of sorivudine therapy, which indicate s that fluorinated pyrimidines may be safely administered 4 weeks afte r completion of sorivudine therapy.