Glucuronidic prodrugs

Perhaps the most promising application of glucuronide prodrugs is targeting the intestine in the treatment of ulcerative colitis and irritable-bowel syn-... 

Similar to glycoside prodrugs are the glucuronide prodrugs containing corticosteroids [53-55], They also show improvements in the therapeutic effect and in the reduction of side effects. 

B. Haeberlin, L. Empey, R. Fedorak, H. Nolen III, and D. Friend, In vivo studies in the evaluation of glucuronide prodrugs for novel therapy of ulcerative colitis, Proceed Intern. Symp. Control. Rel. Bioact. Mater. 20 174-175 (1993). 

Glucuronide prodrugs 58a, 58b, and 59 of 5-fluorouracil exhibited half-lives of 20 minutes when incubated with 25 pg/mL of (3-glucuronidase and reduced (six to nine times less) cytotoxicity against LoVo cells in comparison with the parent drug 5-fluorouracil (Figure 11.9).88... 

Talelli, M., Morita, K., Rijcken, C. J. F., Aben, R. W. M., Lammers, T, Scheeren, H. W., van Nostrum, C. F, Storm, G. and Hennink, W. E. (2011) Synthesis and characterization of biodegradable and thermosensitive polymeric micelles with covalently bound doxorubidn-glucuronide prodrug via click cherrasXry.Bioconiueate Chem, 22,2519-2530. 

The same strategy was applied in colon-specific delivery of two corticosteroids used to treat inflammatory bowel disease [20][21], Indeed, budeso-nide /3-D-glucuronide and dexamethasone /3-D-glucuronide underwent ready hydrolysis in the luminal contents of rat colon and caecum. Rat mucosal homogenates were less active, and hydrolysis in human fecal samples was quite low. Based on these and other studies, the prodrugs were found to be suitable candidates for delivery of corticosteroids to the large intestine. 

UGTIAI has an important role in the metabolism of irinotecan, etoposide, epiru-bicine, and tipifamib. Irinotecan is a camptothecin derivative used in the treatment of metastatic colon cancer. Irinotecan is a prodrug since it is activated to Ethyl-10-hydroxycamptothecin (SN-38) by carboxyl esterase to exert its antitumor activity mediated by the inhibition of topoisomerase I. SN-38 undergoes UGTIAI-catalyzed glucuronide conjugation to form the inactive SN-38 glucuronide (SN-38G). 

The most important other opium alkaloid is codeine. In contrast to morphine, codeine has a high oral-parenteral potency ratio due to less first-pass metabolism. Codeine is considered a prodrug, since it is metabolised in vivo to the primary active compounds morphine and codeine-6-glucuronide. Approximately 10% is demethylated to morphine. The analgesic effect of codeine is due to the formation of these metabolites as codeine itself has a very low affinity for opioid receptors. The half-life of codeine in plasma is 2 hours. 

Irinotecan, an antineoplastic-prodrug, is widely used for the treatment of colorectal, lung and other cancers, and is one of model pharmaceuticals for personalized medicine. The active metabolite, SN-38, is a topoisomerase I inhibitor generated by hydrolysis of irinotecan by carboxylesterases. SN-38 is subsequently glucuronidated... 

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