INTESTINAL ANAEROBIC-BACTERIA HYDROLYZE SORIVUDINE, PRODUCING THE HIGH BLOOD-CONCENTRATION OF 5-(E)-(2-BROMOVINYL)URACIL THAT INCREASES THELEVEL AND TOXICITY OF 5-FLUOROURACIL

Sorivudine, eta-D-arabinofuranosyl-5-(E)-(2-bromovinyl)uracil, is a po tent antiviral agent against varicella-zoster virus and herpes simplex virus type 1. However, sorivudine should not be used in combination w ith anticancer drugs such as 5-fluorouracil (5-FU) because (E)-5-(2-br omovinyl)uracil (BVU), a metabolite of sorivudine, inhibits the degrad ation of 5-FU, resulting in its accumulation in the blood and marked e nhancement of the toxicity of 5-FU. Since phosphorolytic enzymes gener ate BVU from sorivudine, we investigated the distribution of the enzym e activity in rats. High activity was found in the cecal and large int estinal contents, while very low or no detectable activity in the live r, kidney, stomach, cecum, large intestine, and the stomach and small intestinal contents. These results suggest that intestinal microflora play an important role in BVU production. Therefore, we measured the p hosphorylase activity in cell-free extracts from 23 aerobes, 16 anaero bes and a fungus. Bacteroides species B. vulgatus, B. thetaiotaomicron , B. fragilis, B. uniformis and B. eggerthii, dominant members of inte stinal microflora, had high activity to convert sorivudine to BVU. To elucidate the contribution of intestinal microflora to BVU production in vivo, we administered sorivudine to rats treated with several antib iotics and measured the BVU concentration in the serum of rats. When s orivudine was given to rats treated with ampicillin or a mixture of ba citracin, neomycin and streptomycin, which decreased the numbers of vi able aerobes and anaerobes, only a small amount of BVU was found in th e serum. BVU concentration in the serum of rats treated with metronida zole to decrease the number of intestinal anaerobes was also very low. In contrast, BVU concentration in the serum of rats treated with kana mycin, which was used to decrease the number of aerobes selectively, w as higher than that of non-treated rats. These results also suggest th at BVU is produced by intestinal anaerobic bacteria especially Bactero ides species in vivo.