In vitro and in vivo investigation of dexibuprofen derivatives for CNS delivery

Abstract

Aim: Dexibuprofen, the S(+)-isomer of ibuprofen, is an effective therapeutic agent for the treatment of neurodegenerative disorders. However, its clinical use is hampered by a limited brain distribution. The aim of this study was to design and synthesize brain-targeting dexibuprofen prodrugs and to evaluate their brain-targeting efficiency using biodistribution and pharmacokinetic analysis. Methods: In vitro stability, biodistribution and pharmacokinetic studies were performed on male Sprague-Dawley rats. The concentrations of dexibuprofen in biosamples, including the plasma, brain, heart, liver, spleen, lung, and kidney, were measured using high pressure lipid chromatography (HPLC). The pharmacokinetic parameters of the drug in the plasma and tissues were calculated using obtained data and statistics. Results: Five dexibuprofen prodrugs that were modified to contain ethanolamine-related structures were designed and synthesized. Their chemical structures were confirmed using 1 H NMR, 13 C NMR, IR, and HRMS. In the biodistribution study, 10 min after intravenous administration of dexibuprofen (11.70 mg/kg) and its prodrugs (the dose of each compound was equivalent to 11.70 mg/kg of dexibuprofen) in male Sprague-Dawley rats, the dexibuprofen concentrations in the brain and plasma were measured. The C brain /C plasma ratios of prodrugs 1, 2, 3, 4, and 5 were 17.0-, 15.7-, 7.88-, 9.31-, and 3.42-fold higher than that of dexibuprofen, respectively (P<0.01). Thus, each of the prodrugs exhibited a significantly enhanced brain distribution when compared with dexibuprofen. In the pharmacokinetic study, prodrug 1 exhibited a brain-targeting index of 11.19 {DTI=(AUC brain /AUC plasma ) 1 /(AUC brain /AUC plasma ) dexibuprofen }. Conclusion:The ethanolamine-related structures may play an important role in transport across the brain blood barrier.

Mechanism of Brain Targeting by Dexibuprofen Prodrugs Modified with Ethanolamine-Related Structures

“…This is consistent with our previous study of brain targeting by these prodrugs. 18 Uptake characteristics were different for the prodrugs. Uptake of DIBU and of prodrugs III and IV increased linearly with incubation time and concentrations, it did not differ significantly between 37°C and 4°C, and it was not inhibited by sodium azide or rotenone.…”

Simultaneous Determination of NSAID and Antimicrobial Preservatives Using Validated RP-HPLC Method: An Application in Pharmaceutical and Clinical Laboratories

“…[11][12][13], in human serum and other physiologic fluids by HPLC/HPLC-mass spectrometry [14][15][16][17][18][19], by radian compression technique [20].…”

Novel flurbiprofen derivatives with improved brain delivery: synthesis, in vitro and in vivo evaluations

“…Prodrug strategy, one of the medicinal chemistry drug delivery systems, has been investigated extensively in order to increase the targeting efficiency of drugs to the brain (Anderson, 1996). Previous work of our research group demonstrated that ethanolamine-related structure could effectively improve drug availability in the brain (Zhang et al, 2012). In this study, we introduced N,N-dimethylethanolamine ligand, with active transport function, to FLU and developed novel FLU conjugates.…”

“…It was found that drugs conjugated with these ligands could significantly enhance their accumulations in the brain after intravenous (i.v.) injection into rats (Zhang et al, 2012). Ethanolamine-related structures are widely found in either endogenous substances including phosphatidylcholine (e.g.…”

“…neurotransmitters) or various CNS therapeutic agents, such as chlorpromazine, meclofenoxate and procaine. With the amino group, ethanolamine is positively charged in physiological condition, and might become a substrate of the organic cation or choline transporters located at the BBB (Zhang et al, 2012). Moreover, there are several advantages for drug development with this ligand, including a simple, small and well-defined structure, and a lack of toxicity, which contrasts with the toxic effects sometimes reported with polymeric nanocarriers (Ai et al, 2011).…”