title: Mode of action of beta-cyclodextrin as an absorption enhancer of the water-soluble drug meglumine antimoniate.
abstract: It has been previously reported that beta-cyclodextrin (beta-CD) enhances the oral absorption of the pentavalent antimony (Sb) drug, meglumine antimoniate (MA). Contrary to the drugs commonly used in association with beta-CD, MA is highly soluble in water (solubility >300 mg/mL) and, therefore, the mode of action of beta-CD in this system requires clarification. ESI(-)-MS analysis of MA and of the MA/beta-CD composition indicated the formation of a 1:1 association compound between 1:1 Sb-meglumine complex and beta-CD. A stability constant on the order of 100 Lmol(-1) was determined for this association compound. When MA solution was heated for 48 h at 55 degrees C to mimic the conditions used to prepare MA/beta-CD, MA was found to suffer dissociation, from high molecular weight Sb complexes into species of lower molecular weight. Strikingly, heated MA was found to be more extensively absorbed in mice by the oral route than MA freshly prepared at room temperature. In vitro skin permeation experiments using MA and MA/beta-CD indicated a two-fold increase in the Sb flux for MA/beta-CD. These findings support the hypothesis that the improved oral absorption of Sb arises from the increased permeation of MA across lipid bilayers, as a result of the enhanced availability of 1:1 Sb-meglumine complex.
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: Patrícia S
authors.initials: PS
authors.lastname: Martins
authors.forename: Rosemary
authors.initials: R
authors.lastname: Ochoa
authors.forename: Adriano M C
authors.initials: AM
authors.lastname: Pimenta
authors.forename: Lucas A M
authors.initials: LA
authors.lastname: Ferreira
authors.forename: Alan L
authors.initials: AL
authors.lastname: Melo
authors.forename: José B B
authors.initials: JB
authors.lastname: da Silva
authors.forename: Rubén D
authors.initials: RD
authors.lastname: Sinisterra
authors.forename: Cynthia
authors.initials: C
authors.lastname: Demicheli
authors.forename: Frédéric
authors.initials: F
authors.lastname: Frézard
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002942:Circular Dichroism / Q000379:methods; D004355:Drug Stability; D005260:Female; D008051:Lipid Bilayers / Q000378:metabolism; D008536:Meglumine / Q000737:chemistry / Q000493:pharmacokinetics*; D000077485:Meglumine Antimoniate; D051379:Mice; D008970:Molecular Weight; D009942:Organometallic Compounds / Q000737:chemistry / Q000493:pharmacokinetics*; D010539:Permeability; D012867:Skin / Q000187:drug effects / Q000378:metabolism; D012869:Skin Absorption / Q000187:drug effects*; D012995:Solubility; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods; D013696:Temperature; D014867:Water / Q000737:chemistry; D047392:beta-Cyclodextrins / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D008051:Lipid Bilayers; D009942:Organometallic Compounds; D047392:beta-Cyclodextrins; D014867:Water; D008536:Meglumine; D000077485:Meglumine Antimoniate