Ascorbic and 6-Br-ascorbic acid conjugates as a tool to increase the therapeutic effects of potentially central active drugs.
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 [(14)C]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.
Dalpiaz
Alessandro
A
Department of Pharmaceutical Sciences, Ferrara University, via Fossato di Mortara 19, 44100 Ferrara, Italy. dla@dns.unife.it
Pavan
Barbara
B
Vertuani
Silvia
S
Vitali
Federica
F
Scaglianti
Martina
M
Bortolotti
Fabrizio
F
Biondi
Carla
C
Scatturin
Angelo
A
Tanganelli
Sergio
S
Ferraro
Luca
L
Marzola
Giuliano
G
Prasad
Puttur
P
Manfredini
Stefano
S
D000818:Animals; D001205:Ascorbic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D002460:Cell Line; D002491:Central Nervous System Agents / Q000378:metabolism / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D008297:Male; D051379:Mice; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control; D013329:Structure-Activity Relationship
D002491:Central Nervous System Agents; C068572:6-deoxy-6-bromoascorbic acid; D001205:Ascorbic Acid