TY - JOUR
T1 - Ascorbic and 6-Br-ascorbic acid conjugates as a tool to increase the therapeutic effects of potentially central active drugs
AU - Dalpiaz, Alessandro
AU - Pavan, Barbara
AU - Vertuani, Silvia
AU - Vitali, Federica
AU - Scaglianti, Martina
AU - Bortolotti, Fabrizio
AU - Biondi, Carla
AU - Scatturin, Angelo
AU - Tanganelli, Sergio
AU - Ferraro, Luca
AU - Marzola, Giuliano
AU - Prasad, Puttur
AU - Manfredini, Stefano
N1 - Funding Information:
This work was supported by University of Ferrara and National Institutes of Health Grant (HD37150).
PY - 2005/3
Y1 - 2005/3
N2 - Ascorbic acid (AA) or 6-Br-ascorbate (BrAA) conjugation has been investigated as a tool to improve brain drug delivery by the Vitamin C transporter SVCT2. To this aim, the effects of AA- or BrAA-conjugation on drug affinity and uptake have been assessed in vitro, by using human retinal pigment epithelium (HRPE) cells, and compared in vivo on mice. Nipecotic, kynurenic and diclofenamic acids were chosen as model drugs. Kinetic and inhibition experiments referred to [14C]AA uptake into HRPE cells showed that nipecotic and kynurenic acids became able to interact with SVCT2, as competitive inhibitors, only when conjugated to AA or BrAA. Surprisingly, diclofenamic acid itself appeared able to interact with SVCT2, with an affinity that was significantly increased or decreased by AA or BrAA conjugation, respectively. HPLC analysis, performed on HRPE cells, confirmed the SVCT2 mediated transport for the BrAA-conjugate of nipecotic acid, whereas kynurenic acids conjugates although interacting with the transporter did not enter the cells. In accordance, only the nipecotic acid conjugates showed anticonvulsant activity after systemic injection in mice.
AB - Ascorbic acid (AA) or 6-Br-ascorbate (BrAA) conjugation has been investigated as a tool to improve brain drug delivery by the Vitamin C transporter SVCT2. To this aim, the effects of AA- or BrAA-conjugation on drug affinity and uptake have been assessed in vitro, by using human retinal pigment epithelium (HRPE) cells, and compared in vivo on mice. Nipecotic, kynurenic and diclofenamic acids were chosen as model drugs. Kinetic and inhibition experiments referred to [14C]AA uptake into HRPE cells showed that nipecotic and kynurenic acids became able to interact with SVCT2, as competitive inhibitors, only when conjugated to AA or BrAA. Surprisingly, diclofenamic acid itself appeared able to interact with SVCT2, with an affinity that was significantly increased or decreased by AA or BrAA conjugation, respectively. HPLC analysis, performed on HRPE cells, confirmed the SVCT2 mediated transport for the BrAA-conjugate of nipecotic acid, whereas kynurenic acids conjugates although interacting with the transporter did not enter the cells. In accordance, only the nipecotic acid conjugates showed anticonvulsant activity after systemic injection in mice.
KW - Brain delivery
KW - Drug targeting
KW - HRPE cells
KW - SVCT2 transporter
KW - Vitamin C
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U2 - 10.1016/j.ejps.2004.10.014
DO - 10.1016/j.ejps.2004.10.014
M3 - Article
C2 - 15734292
AN - SCOPUS:20044368980
SN - 0928-0987
VL - 24
SP - 259
EP - 269
JO - European Journal of Pharmaceutical Sciences
JF - European Journal of Pharmaceutical Sciences
IS - 4
ER -