Sorivudine and 5-fluorouracil; a clinically significant drug-drug interaction due to inhibition of dihydropyrimidine dehydrogenase

Abstract

Sorivudine (1-beta-D-arabinofuranosyl-E-5-[2-bromovinyl] uracil; BV-araU; SQ32,756) is an antimetabolite which is a synthetic analogue of thymidine. This drug has demonstrated antiviral activity against varicella zoster virus, herpes simplex type 1 virus, and Epstein-Barr virus. Clinical studies in Japan and subsequently worldwide showed this drug to be a potent agent for treating varicella zoster infections. Although in general well tolerated, a fatal drug interaction with fluoropyrimidine drugs was subsequently observed. While three deaths resulting from this interaction were recognized to have occurred during the initial clinical evaluation in Japan, the full impact of the interaction was not recognized in Japan until post-marketing when an additional 23 cases of severe toxicity were reported including 16 patients who subsequently died from fluoro-pyrimidine toxicity. Worldwide recognition of this potentially fatal drug-drug interaction led to subsequent disapproval in the US and elsewhere. The interaction has been shown to be due to suppression of 5-fluorouracil (5-FU) catabolism, resulting in higher levels of 5-FU than would normally be observed. The mechanism of this interaction is mediated through inhibition of the 5-FU rate-limiting catabolizing enzyme dihydropyrmidine dehydrogenase (DPD) by the BV-araU metabolite BVU. This drug-drug interaction of sorivudine and 5-FU further emphasizes the critical importance of DPD on the clinical pharmacology of 5-FU.

Figure 1

Structure of sorivudine (1-β-d-arabinofuranosyl-E-5-[2-bromovinyl] uracil; BV-araU; SQ32,756).

Figure 2

Metabolic overview illustrating the critical position of DPD in the metabolism of 5-FU as well as the natural pyrimidines uracil and thymine. More than 85% of administered 5-FU is catabolized via DPD. (Abbreviations: FUH2—dihydrofluorouracil; FUPA—fluoro-ureidopropionic acid; FBAL—Fluoro-beta- alanine; FUrd—Fluorouridine; FUMP -Fluoro- uridine monophosphate; FUDP—Fluorouridine diphosphate; FUTP—Fluoro uridine triphosphate; FUdR—Fluorodeoxyuridine; FdUMP—Fluorodeoxyuridine monophosphate; FdUDP—Fluorodeoxyuridine diphosphate; FdUTP—Fluorodeoxyuridine triphosphate; BVU—bromovinyl uracil).