The effect of sorivudine on dihydropyrimidine dehydrogenase activity in patients with acute herpes zoster.
OBJECTIVE
Bromovinyl-uracil (BVU) is the principal metabolite of sorivudine, a potent anti-zoster nucleoside. BVU binds to, and irreversibly inhibits, the enzyme dihydropyrimidine dehydrogenase (DPD). The objective of this study was to assess the time course of recovery of DPD activity after oral administration of sorivudine in patients with herpes zoster and to correlate restoration of DPD activity and levels of uracil with the elimination of sorivudine and its metabolite BVU from the circulation.


METHODS
Sorivudine was given orally as 40 mg once-daily doses for 10 consecutive days to a total of 19 patients with herpes zoster. Serum sorivudine, BVU, and circulating uracil and DPD activity in peripheral blood mononuclear cells (PBMCs) were determined before, during, and after administration of sorivudine.


RESULTS
BVU was eliminated from the circulation within 7 days after the last sorivudine dose. DPD activity in PBMCs, which was completely suppressed in 18 of the 19 subjects and markedly suppressed in the remaining subject during administration of sorivudine, recovered to baseline levels within 19 days after the last dose of sorivudine in all subjects and within 14 days in all but one of the subjects. The restoration of DPD activity was temporally associated with elimination of BVU from the circulation. The elevated uracil concentrations produced by inhibition of DPD activity fell rapidly after cessation of sorivudine administration and also were temporally associated with elimination of BVU from the circulation. The time course of recovery of DPD activity in three patients with renal impairment was similar to that of the other subjects.


CONCLUSIONS
This study indicates that sorivudine therapy is associated with a profound depression of DPD activity. Recovery of DPD activity occurred within 4 weeks of the completion of sorivudine therapy, which indicates that fluorinated pyrimidines may be safely administered 4 weeks after completion of sorivudine therapy.
Yan
J
J
Department of Pharmacology and Toxicology, University of Alabama at Birmingham 35294, USA.
Tyring
S K
SK
McCrary
M M
MM
Lee
P C
PC
Haworth
S
S
Raymond
R
R
Olsen
S J
SJ
Diasio
R B
RB
D000208:Acute Disease; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D000998:Antiviral Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001086:Arabinofuranosyluracil / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D001976:Bromouracil / Q000031:analogs & derivatives / Q000097:blood; D002851:Chromatography, High Pressure Liquid; D042943:Dihydrouracil Dehydrogenase (NADP); D005260:Female; D006562:Herpes Zoster / Q000188:drug therapy / Q000201:enzymology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010088:Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012984:Software; D014498:Uracil / Q000097:blood
D000998:Antiviral Agents; D001086:Arabinofuranosyluracil; D001976:Bromouracil; D014498:Uracil; C046140:5-(2-bromovinyl)uracil; C031368:sorivudine; D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP)