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.

Figure 1

HPLC chromatograms of dexibuprofen and prodrugs 1, 2, 3, 4, and 5. Compound was dissolved in methanol with concentration of 5 μg/mL.

Figure 2

Dexibuprofen concentrations (μg/g) in the plasma and brain 10 min after intravenous administration of dexibuprofen (11.70 mg/kg) or prodrugs 1, 2, 3, 4, 5 (each compound was equivalent to 11.70 mg/kg of dexibuprofen) in rats. Each point represents the mean±SD of five experiments. ^cP<0.01 vs dexibuprofen.

Figure 3

Comparison of (C_brain/C_plasma)_dexibuprofen ratios of dexibuprofen and prodrugs. C_brain, C_plasma: dexibuprofen concentration (μg/g) in the brain or plasma 10 min after intravenous administration of dexibuprofen (11.70 mg/kg) or prodrugs 1, 2, 3, 4, 5 (each compound was equivalent to 11.70 mg/kg of dexibuprofen) in rats. Each point represents the mean±SD of five experiments. ^cP<0.01 vs dexibuprofen.

Figure 4

Dexibuprofen concentrations in the plasma and brain (μg/g) vs time (h) after intravenous administration of dexibuprofen (11.70 mg/kg) and prodrug 1 (15.73 mg/kg, equivalent to 11.70 mg/kg of dexibuprofen) in rats. Each point represents the mean±SD of five experiments. ^bP<0.05, ^cP<0.01 vs dexibuprofen.

Figure 5

(C_brain/C_plasma)_dexibuprofen ratios of dexibuprofen or prodrug 1 versus time (h). C_brain, C_plasma: dexibuprofen concentration (μg/g) in the brain or plasma after intravenous administration of dexibuprofen (11.70 mg/kg) or prodrug 1 (15.73 mg/kg, equivalent to 11.70 mg/kg of dexibuprofen) in rats. Each point represents the mean±SD of five experiments. ^bP<0.05, ^cP<0.01 vs dexibuprofen.

Scheme 1

Synthesis of dexibuprofen derivatives modified by ethanolamine related structures (1, 2, 3, 4, 5). Reagents and conditions: (a) CH₂Cl₂, TEA; (b) (Boc)₂O, NaOH; (c) dexibuprofen chloride, TEA; (d) EtOAc, HCl, RT; (e) CH₃COCl, NaH, dioxane; (f) dexibuprofen chloride, TEA.