SORIVUDINE AND 5-FLUOROURACIL - A CLINICALLY SIGNIFICANT DRUG-DRUG INTERACTION DUE TO INHIBITION OF DIHYDROPYRIMIDINE DEHYDROGENASE

(1-beta-D-arabinofuranosyl-E-5-[2-bromovinyl] uracil; BV-araU; SQ32,75 6) is an antimetabolite which is a synthetic analogue of thymidine. Th is drug has demonstrated antiviral activity against varicella tester v irus, herpes simplex type 1 virus, and Epstein-Barr virus. Clinical st udies in Japan and subsequently worldwide showed this drug to be a pot ent agent for treating varicella tester infections. Although in genera l well tolerated, a fatal drug interaction with fluoropyrimidine drugs was subsequently observed. While three deaths resulting from this int eraction were recognized to have occurred during the initial clinical evaluation in Japan, the full impact of the interaction was not recogn ized in Japan until post-marketing when an additional 23 cases of seve re toxicity were reported including 16 patients who subsequently died from fluoro-pyrimidine toxicity. Worldwide recognition of this potenti ally fatal drug-drug interaction led to subsequent disapproval in the US and elsewhere. The interaction has been shown to be due to suppress ion of 5-fluorouracil (5-FU) catabolism, resulting in higher levels of 5-FU than would normally be observed. The mechanism of this interacti on is mediated through inhibition of the 5-FU rate-limiting catabolizi ng enzyme dihydropyrimidine dehydrogenase (DPD) by the BV-araU metabol ite BVU. This drug-drug interaction of sorivudine and 5-FU further emp hasizes the critical importance of DPD on the clinical pharmacology of 5-FU.