COLON-SPECIFIC PRODRUGS OF 5-RADIOIODO-2'-DEOXYURIDINE

Two glycoside-based prodrugs, (125)IUdR-5'-beta-D-glucopyranoside and (125)IUdR-5'-beta-D-galactopyranoside, were synthesized. This selectio n was dictated by the abundance of appropriate enzymes in the GI tract of mice and similar levels of beta-D-glycosidases in human and rodent large intestine. Studies to establish the ability of colonic microflo ra to release (125)IUdR were conducted in vitro and in Swiss Webster m ice. Both prodrugs released (125)IUdR in the presence of the correspon ding enzymes or the GI content homogenates in vitro, and in vivo. Lumi nal enzymes in the proximal and distal small intestine in mice degrade d less than 10% of each prodrug whereas enzymes from the colonic/caeca l lumen of mice released nearly 100% of (125)IUdR. (125)IUdR freed by bacterial glycosidases was stable in the GI content. No significant am ounts of other metabolites or deiodination products were observed. Tot al radioactivity recovered as by-products was less than 10%. The efflu x of prodrugs from the GI tract after oral administration in mice was slow and limited. Unlike (125)IUdR, prodrugs were not dehalogenated in vivo as indicated by biodistribution and imaging studies.