Transporter-mediated effects of diclofenamic acid and its ascorbyl pro-drug in the in vivo neurotropic activity of ascorbyl nipecotic acid conjugate
✍ Scribed by Alessandro Dalpiaz; Barbara Pavan; Martina Scaglianti; Federica Vitali; Fabrizio Bortolotti; Carla Biondi; Angelo Scatturin; Sergio Tanganelli; Luca Ferraro; Puttur Prasad; Stefano Manfredini
- Publisher
- John Wiley and Sons
- Year
- 2004
- Tongue
- English
- Weight
- 136 KB
- Volume
- 93
- Category
- Article
- ISSN
- 0022-3549
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✦ Synopsis
Continuing our studies on SVCT2 ascorbic acid (AA) transporter-mediated drug delivery of neurotropic agents, we have now investigated the in vitro intracellular uptake of Diclofenac (Diclo) and its conjugate (AA-Diclo), both characterized by high affinity for the SVCT2 transporter. We have also investigated the in vivo uptake mechanism of AA-conjugate of Nipecotic acid (AA-Nipec) and the implication of the transporter-mediated effects of Diclo and AA-Diclo. Diclo resulted as a noncompetitive inhibitor of AA transport, but also showed a sodium-dependent and ascorbateindependent uptake, thus implying the possible involvement of specific transporters in the delivery to the brain of Diclo. This result opens a perspective in the discovery of new strategies in the targeting of this drug to the brain. Inhibitory effects of Diclo and AA-Diclo on the SVCT2 transporter were used to study anticonvulsant effects of AA-Nipec, confirming our hypothesis of an SVCT2-mediated transport in its neurotropic activity. AA-Diclo stability has been also investigated: it is hydrolyzed following a first-order kinetics in buffer, plasma (t 1/2 at about 10 h) and whole blood (t 1/2 at about 3 h), suggesting AA-Diclo as a potential candidate to enhance the short half-life of Diclo in vivo.