Synthesis, in vitro and in vivo characterization of glycosyl derivatives of ibuprofen as novel prodrugs for brain drug delivery.

New glycosyl derivatives of ibuprofen (I, II, III, and IV) were synthesized in order to overcome the ineffective delivery of ibuprofen across the blood-brain barrier owing to its low permeability, using d-glucose as a drug targeting agent. Ibuprofen was linked directly to the C-2, C-3, C-4, and C-6 positions of glucose via ester bonds. Furthermore, in vitro stabilities of the four ester derivatives were evaluated to determine both their stability in aqueous medium and their feasibility to undergo enzymatic cleavage by esterase in biological samples to regenerate the original drug. From the obtained results, compounds I-IV appeared to be moderately stable in pH 7.43 buffer solution, rat plasma, and brain tissue extracts. In vivo experiments showed that the AUC(0-)(t) of ibuprofen in plasma after the injection of prodrugs is several times higher than that of AUC(0-)(t) after the injection of ibuprofen. In addition, the maximal concentration of ibuprofen in brain after the administration of ester IV was three fold higher than that of the control group. Also, the concentration of ibuprofen was kept stable in brain for about 4 h for four esters, which was beneficial for the treatment of Alzheimer's disease and highlighted the possibility of brain drug delivery of ibuprofen using prodrug strategies.