Colon-Specific Prodrugs of 5-Radioiodo-2'-Deoxyuridine

Abstract

Two glycoside-based prodrugs, ¹²⁵IUdR-5'-β-D-glucopyranoside and ¹²⁵IUdR-5'-β-D-galactopyranoside, were synthesized. This selection was dictated by the abundance of appropriate enzymes in the GI tract of mice and similar levels of β-D-glycosidases in human and rodent large intestine. Studies to establish the ability of colonic microflora to release ¹²⁵IUdR were conducted in vitro and in Swiss Webster mice. Both prodrugs released ¹²⁵IUdR in the presence of the corresponding enzymes or the GI content homogenates in vitro, and in vivo. Luminal enzymes in the proximal and distal small intestine in mice degraded less than 10% of each prodrug whereas enzymes from the colonic/caecal lumen of mice released nearly 100% of ¹²⁵IUdR. ¹²⁵IUdR freed by bacterial glycosidases was stable in the GI content. No significant amounts of other metabolites or deiodination products were observed. Total radioactivity recovered as by-products was less than 10%. The efflux of prodrugs from the GI tract after oral administration in mice was slow and limited. Unlike ¹²⁵IUdR, prodrugs were not dehalogenated in vivo as indicated by biodistribution and imaging studies.