title: Prolonged absorption of antimony(V) by the oral route from non-inclusion meglumine antimoniate-beta-cyclodextrin conjugates.
abstract: The orally active composition comprising meglumine antimoniate (MA) and beta-cyclodextrin (beta-CD) differs markedly from conventional drug-CD complexes, since it combines a water-soluble drug and a hydrophilic CD. In order to obtain insights into the mechanism(s) responsible for the improved oral delivery of the drug, physicochemical and pharmacokinetic studies were carried out. The composition investigated here was prepared at a 7:1 antimony(Sb)/beta-CD molar ratio, a condition that improves its solubility in water and allows the oral administration of a high dose of Sb in large animals. It was characterized by circular dichroism, (1)H-NMR, ESI-MS and photon correlation spectroscopy. Pharmacokinetic data were obtained in Beagle dogs after oral administration of the composition at 100 mg Sb/kg. (1)H-NMR and ESI-MS data supported the formation of non-inclusion complexes between MA and beta-CD. Sub-micron assemblies were also evidenced that slowly dissociate and presumably release the MA drug, upon reconstitution of the composition in water. Pharmacokinetic studies of MA and MA/beta-CD in dogs showed a prolongation of the serum mean residence time of Sb from 4.1 to 6.8 h, upon complexation of MA with beta-CD. Evidence was also obtained that Sb remains essentially under the form of pentavalent Sb-meglumine complex, following gastro-intestinal absorption from the MA/beta-CD composition. In conclusion, the present data support the model that the sustained drug release property of 7:1 MA/beta-CD composition resulted in the prolongation of MA absorption by the oral route and, consequently, in the increase of the drug mean residence time in serum.
authors.affiliation: Departamento de Fisiologia e Biofísica, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Av. Antônio Carlos 6627, Pampulha, 31270-901 Belo Horizonte, MG, Brazil.
authors.forename: Raul R
authors.initials: RR
authors.lastname: Ribeiro
authors.forename: Weverson A
authors.initials: WA
authors.lastname: Ferreira
authors.forename: Patricia S
authors.initials: PS
authors.lastname: Martins
authors.forename: Rubens L M
authors.initials: RL
authors.lastname: Neto
authors.forename: Olguita G F
authors.initials: OG
authors.lastname: Rocha
authors.forename: Laurence
authors.initials: L
authors.lastname: Le Moyec
authors.forename: Cynthia
authors.initials: C
authors.lastname: Demicheli
authors.forename: Frédéric
authors.initials: F
authors.lastname: Frézard
mesh_terms: D000042:Absorption; D000284:Administration, Oral; D000818:Animals; D000965:Antimony / Q000493:pharmacokinetics*; D002942:Circular Dichroism; D003692:Delayed-Action Preparations; D004285:Dogs; D005260:Female; D008297:Male; D008536:Meglumine / Q000737:chemistry* / Q000493:pharmacokinetics; D000077485:Meglumine Antimoniate; D051379:Mice; D009942:Organometallic Compounds / Q000493:pharmacokinetics*; D047392:beta-Cyclodextrins / Q000493:pharmacokinetics*
chemical_list: D003692:Delayed-Action Preparations; D009942:Organometallic Compounds; D047392:beta-Cyclodextrins; D008536:Meglumine; D000077485:Meglumine Antimoniate; D000965:Antimony; C031215:betadex