title: Physicochemical, pharmacological and pharmacokinetic study of a new GABAergic compound, calcium acetylhomotaurinate.
abstract: It has been shown that calcium acetylhomotaurinate (Ca AOTA; Meram Patent, France) decreased voluntary ethanol intake in rats (1); this was antagonized by bicuculline. Homotaurine did not have this effect. We thought this was due to a different blood-brain barrier crossing ability for the two drugs. The present study was, therefore, planned to confirm blood-barrier crossing by Ca AOTA and to study the drug's physicochemical and pharmacokinetic characteristics. Both in vitro and in vivo (i.p.) administration of Ca AOTA increased the accumulation of [3H] GABA in rat striatal synaptosomal preparations. The chemical study confirmed Ca AOTA's great stability in biological and hydrophilic media, excluding a "homotaurine-dispensing" effect. The molecule was totally dissociated in such media, but the absence of any detectable acid form at any pH indicates that ion pairs are formed to cross barriers, and/or that a carrier system is used. The pharmacokinetic study showed short half-lives (5 and 30 min for the distribution and elimination phases) and small distribution volumes. However, the elimination phase distribution volume was dose-dependent, a further argument for a carrier transport system. From the present study it appears that Ca AOTA is an extremely stable drug, totally dissociated in hydrophilic media, which acts centrally as a GABA agonist after crossing the blood-brain barrier. It is not a precursor of homotaurine and presumably crosses barriers with the help of a transporter.
authors.affiliation: Centre de Pharmacochimie, UER de Médecine-Pharmacie de Rouen, Saint-Etienne du Rouvray, France.
authors.forename: C
authors.initials: C
authors.lastname: Chabenat
authors.forename: P
authors.initials: P
authors.lastname: Chretien
authors.forename: M
authors.initials: M
authors.lastname: Daoust
authors.forename: N
authors.initials: N
authors.lastname: Moore
authors.forename: D
authors.initials: D
authors.lastname: Andre
authors.forename: J P
authors.initials: JP
authors.lastname: Lhuintre
authors.forename: C
authors.initials: C
authors.lastname: Saligaut
authors.forename: P
authors.initials: P
authors.lastname: Boucly
authors.forename: F
authors.initials: F
authors.lastname: Boismare
mesh_terms: D000077443:Acamprosate; D000818:Animals; D001812:Blood-Brain Barrier; D003342:Corpus Striatum / Q000378:metabolism; D008297:Male; D051381:Rats; D013654:Taurine / Q000031:analogs & derivatives* / Q000032:analysis / Q000493:pharmacokinetics / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D013654:Taurine; D005680:gamma-Aminobutyric Acid; D000077443:Acamprosate