title: Diclofenac-β-cyclodextrin for colonic drug targeting: In vivo performance in rats.
abstract: The aim of this in vivo study was to assess the ability of the prodrug conjugate diclofenac-β-cyclodextrin to release diclofenac in the colon following oral administration, using sulfapyridine (a metabolite of sulfasalazine) as a marker of colonic absorption. Two groups of rats were used; the test rats received a suspension containing the two prodrugs, diclofenac-β-cyclodextrin and sulfasalazine, while the control rats received a suspension containing the corresponding free drugs, sodium diclofenac and sulfapyridine. The rats were fasted overnight with free access to water before and throughout the first 12h of the study. Blood was collected from the tail vein at pre-determined time points and the plasma analyzed for the concentrations of diclofenac and sulfapyridine. Following the oral administration of the two prodrugs, a more extended absorption profile was observed and Cmax was achieved 10h post-dose, in contrast to rapid absorption of the free drugs (tmax of diclofenac being 1.3h, and that of sulfapyridine being 2.1h). In addition to a later tmax, conjugation of diclofenac to β-cyclodextrin also resulted in a reduced Cmax and a reduced AUC. The same tmax for diclofenac-β-cyclodextrin as for sulfasalazine confirms the colonic metabolism of diclofenac-β-cyclodextrin. This study shows the potential of this new cyclodextrin-based prodrug to target and release diclofenac specifically in the colon following oral administration.
authors.affiliation: Department of Pharmaceutics, UCL School of Pharmacy, London, United Kingdom; Centre for Pharmaceutical Studies, Laboratory of Pharmaceutical Science, Faculty of Pharmacy, University of Coimbra, Portugal; Chymiotechnon and Department of Chemistry, Faculty of Science and Technology, University of Coimbra, Portugal.
authors.forename: Amélia C F
authors.initials: AC
authors.lastname: Vieira
authors.affiliation: Chymiotechnon and Department of Chemistry, Faculty of Science and Technology, University of Coimbra, Portugal.
authors.forename: Arménio C
authors.initials: AC
authors.lastname: Serra
authors.affiliation: Centre for Pharmaceutical Studies, Laboratory of Pharmaceutical Science, Faculty of Pharmacy, University of Coimbra, Portugal.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Veiga
authors.affiliation: Chymiotechnon and Department of Chemistry, Faculty of Science and Technology, University of Coimbra, Portugal.
authors.forename: António M d'A Rocha
authors.initials: AM
authors.lastname: Gonsalves
authors.affiliation: Department of Pharmaceutics, UCL School of Pharmacy, London, United Kingdom.
authors.forename: Abdul W
authors.initials: AW
authors.lastname: Basit
authors.affiliation: Department of Pharmaceutics, UCL School of Pharmacy, London, United Kingdom. Electronic address: s.murdan@ucl.ac.uk.
authors.forename: Sudaxshina
authors.initials: S
authors.lastname: Murdan
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D003106:Colon / Q000378:metabolism*; D004008:Diclofenac / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D016503:Drug Delivery Systems; D065546:Drug Liberation; D007408:Intestinal Absorption; D008297:Male; D011355:Prodrugs / Q000008:administration & dosage* / Q000032:analysis / Q000737:chemistry / Q000493:pharmacokinetics; D017208:Rats, Wistar; D012460:Sulfasalazine / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D047392:beta-Cyclodextrins / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D011355:Prodrugs; D047392:beta-Cyclodextrins; D004008:Diclofenac; D012460:Sulfasalazine; C031215:betadex
keywords: Colonic targeting; Conjugate; Cyclodextrin; Gut; Large intestine; Microbiota