Transporter-mediated effects of diclofenamic acid and its ascorbyl pro-drug in the in vivo neurotropic activity of ascorbyl nipecotic acid conjugate.
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 ascorbate-independent 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.
Dalpiaz
Alessandro
A
Department of Pharmaceutical Chemistry, via Fossato di Mortara 19, 44100, Ferrara University, I-44100 Ferrara, Italy. dla@dns.unife.it
Pavan
Barbara
B
Scaglianti
Martina
M
Vitali
Federica
F
Bortolotti
Fabrizio
F
Biondi
Carla
C
Scatturin
Angelo
A
Tanganelli
Sergio
S
Ferraro
Luca
L
Prasad
Puttur
P
Manfredini
Stefano
S
D000818:Animals; D001205:Ascorbic Acid / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D004008:Diclofenac / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D051379:Mice; D009557:Nipecotic Acids / Q000493:pharmacokinetics* / Q000627:therapeutic use; D029363:Organic Anion Transporters, Sodium-Dependent / Q000378:metabolism*; D011355:Prodrugs / Q000493:pharmacokinetics* / Q000627:therapeutic use; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control; D060347:Sodium-Coupled Vitamin C Transporters; D027981:Symporters / Q000378:metabolism*
D009557:Nipecotic Acids; D029363:Organic Anion Transporters, Sodium-Dependent; D011355:Prodrugs; C555163:SLC23A2 protein, human; C555165:Slc23a2 protein, mouse; D060347:Sodium-Coupled Vitamin C Transporters; D027981:Symporters; D004008:Diclofenac; C030278:nipecotic acid; D001205:Ascorbic Acid