title: Pharmacokinetic parameters and a theoretical study about metabolism of BR-AEA (a salbutamol derivative) in rabbit.
abstract: In this study, we report the pharmacokinetics of 1-(4-di-hydroxy-3,5-dioxa-4-borabicyclo[4.4.0]deca-7,9,11- trien-9-yl)-2-(tert-butylamino)ethanol (BR-AEA). This compound was identified as a more potent beta(2) adrenoceptor (beta(2)AR) agonist than salbutamol. A sensitive and reproducible high-performance liquid chromatography (HPLC) method was used for determining the time-dependent BR-AEA concentration in healthy rabbit plasma. The pharmacokinetic parameters obtained are explained in relation to the compound's metabolism by sulfotransferases. For this purpose, docking simulations were carried out on SULT1A3, SULT1C1, and SULT1A1 3-D models using the Autodock 3.0.5 program. According to the HPLC results, t(1/2) = 2.36 +/- 0.18 h and K(e) = 0.32 +/- 0.02 h(-1) for BR-AEA in rabbit plasma. Thus, BR-AEA has a greater half-life compared with salbutamol (t(1/2) = 0.66 +/- 0.08 h). This could be due to the protection that the boronic acid moiety of BR-AEA offers to the hydroxyl groups that would otherwise be susceptible to sulfation when exposed inside the active site of the sulfotransferase. This could be due to the fact that BR-AEA has a high affinity for the side-chain hydroxyl groups of Ser and Tyr residues of the enzymes, which are located outside the active site.
authors.affiliation: Physiology and Pharmacology, Escuela Superior de Medicina, IPN, Mexico City, Mexico.
authors.forename: Marvin Antonio
authors.initials: MA
authors.lastname: Soriano-Ursúa
authors.forename: Jose
authors.initials: J
authors.lastname: Correa-Basurto
authors.forename: Juan
authors.initials: J
authors.lastname: Romero-Huerta
authors.forename: Octavio
authors.initials: O
authors.lastname: Elizalde-Solis
authors.forename: Luis Alejandro
authors.initials: LA
authors.lastname: Galicia-Luna
authors.forename: Jose Guadalupe
authors.initials: JG
authors.lastname: Trujillo-Ferrara
mesh_terms: D000318:Adrenergic beta-Agonists; D000420:Albuterol / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics; D000818:Animals; D006207:Half-Life; D008660:Metabolism; D008962:Models, Theoretical; D010599:Pharmacokinetics; D011485:Protein Binding; D011817:Rabbits; D013329:Structure-Activity Relationship; D015238:Sulfotransferases / Q000378:metabolism
chemical_list: C542224:1-(4-di-hydroxy-3,5-dioxa-4-borabicyclo(4.4.0)deca-7,9,11-trien-9-yl)-2-(tert-butylamino)ethanol; D000318:Adrenergic beta-Agonists; D015238:Sulfotransferases; D000420:Albuterol