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 β₂ adrenoceptor (β₂AR) 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 ± 0.08h). 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.

Keywords::

• Salbutamol derivative
• boron
• β₂ adrenoceptor agonist
• pharmacokinetic parameters
• sulfotransferases

Acknowledgments

We thank Bruce Allan Larsen for his revision of the use of English in this article.

Declaration of interest: We are grateful to CONACyT (62488), COFAA, and SIP-IPN (20080026) for financial support to the authors.