title: Azo-reductase activated budesodine prodrugs for colon targeting.
abstract: Budesodine is a synthetic glurocorticoid that undergoes substantial first pass metabolism, limiting systemic exposure. Its use in treatment of inflammatory bowel disease would benefit from a targeting strategy that could lead to a local topical effect, improving safety and increasing anti-inflammatory efficacy. A two-step prodrug strategy involving azoreduction/cyclization that we developed previously for prednisolone is here applied with some variations to budesonide. The budesodine prodrugs were tested using an in vitro azoreductase assay simulating human colonic microflora. The kinetics of amino steroid ester cyclization and its pH dependence was also evaluated. The stability of the prodrugs systems in simulated human duodenal and gastric fluid was evaluated to determine the likelihood of intact intestinal transit. The propionic acid derived prodrug 3 undergoes rapid activation by Clostridium perfingens and its putative reduction product cyclizes with acceptable rapidity when synthesized independently. These properties of 3 suggest that it has potential in management of ulcerative colitis.
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Trinity College, Dublin 2, Ireland.
authors.forename: Juan F
authors.initials: JF
authors.lastname: Marquez Ruiz
authors.forename: Kinga
authors.initials: K
authors.lastname: Kedziora
authors.forename: Mary
authors.initials: M
authors.lastname: O'Reilly
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Maguire
authors.forename: Brian
authors.initials: B
authors.lastname: Keogh
authors.forename: Henry
authors.initials: H
authors.lastname: Windle
authors.forename: Dermot P
authors.initials: DP
authors.lastname: Kelleher
authors.forename: John F
authors.initials: JF
authors.lastname: Gilmer
mesh_terms: D019819:Budesonide / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism*; D003016:Clostridium perfringens; D003093:Colitis, Ulcerative / Q000188:drug therapy / Q000378:metabolism; D003106:Colon / Q000378:metabolism* / Q000382:microbiology; D003500:Cyclization; D016503:Drug Delivery Systems; D006801:Humans; D015394:Molecular Structure; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism*; D009601:Nitroreductases; D009928:Organ Specificity; D011355:Prodrugs / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics*
chemical_list: D011355:Prodrugs; D019819:Budesonide; D009247:NADH, NADPH Oxidoreductases; D009601:Nitroreductases; C021106:azoreductase