GLUT1-mediated venlafaxine-TDS-glucose conjugates with “lock-in” function for CNS delivery

Abstract

Venlafaxine, a novel third generation antidepressant drug, has been described as a reference treatment for major depression in clinical, owing to its ability of inhibiting both noradrenalin and serotonin neuronal reuptake, and inhibiting dopamine reuptake slightly. However, its clinical application is hampered by a limited brain distribution. Glucosylation is an effective way to enhance the brain targeting ability of drugs, but the bidirectional transport of glucose transporter 1 (GLUT₁) might decrease the concentrations of venlafaxine-glucose (V-G) in brain before the release of parent drug venlafaxine. To conquer this drawback of GLUT₁, "lock-in" thiamine disulfide system (TDS) was introduced to modify the V-G conjugate. Both conjugates could release venlafaxine when incubated with the various buffers, mice plasma and brain homogenate. The evaluation in vivo demonstrated that venlafaxine-TDS-glucose (V-TDS-G) had an improved targeting ability and significantly increased the level of venlafaxine in brain compared to the naked venlafaxine and V-G. The relative uptake efficiency (RE) and concentration efficiency (CE) were enhanced to 5.69 and 5.70 times higher than that of naked venlafaxine, respectively. The results of this study suggest that the conjugate strategy based on the glucose-TDS (G-TDS) is available to enhance the delivery of central nervous system (CNS) drugs into brain.

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A novel venlafaxine conjugate V-TDS-G was designed and synthesized in this work. The evaluation in vivo demonstrated that V-TDS-G had an improved targeting ability. which indicated that the G-TDS could act as a vector to enhance the delivery of CNS drugs into brain.

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