TY - JOUR
T1 - Pharmacokinetic analysis and anticonvulsant activity of two polyesteric prodrugs of valproic acid
AU - Hadad, Salim
AU - Vree, Tom B.
AU - Van Der Kleijn, Eppo
AU - Bialer, Meir
PY - 1993/1
Y1 - 1993/1
N2 - The pharmacokinetics of the following two polyesteric prodrugs of valproic acid (VPA) have been investigated: 1,4‐butanediol divaiproate (BDV) and glyceryl trivalproate (GTV). In addition, the anticonvulsant activity of these compounds has been evaluated and compared to that of VPA and valpromide (VPD). Valproic acid, and its two esteric derivatives were administered intravenously to six dogs at an equivalent dose (400 mg VPA) and their pharmacokinetics investigated. In the case of BDV, the biotransformation to VPA was complete, but in the case of GTV, it was only partial. Of the two investigated esteric prodrugs of VPA, only BDV demonstrated anticonvulsant activity and showed less neurotoxicity than VPA and VPD, and therefore had a better protective index. The anticonvulsant activity is explained on pharmacokinetic and pharmacodynamic grounds due to its complete conversion to VPA and the possible synergism in anticonvulsant activity between VPA and 1,4‐butanediol.
AB - The pharmacokinetics of the following two polyesteric prodrugs of valproic acid (VPA) have been investigated: 1,4‐butanediol divaiproate (BDV) and glyceryl trivalproate (GTV). In addition, the anticonvulsant activity of these compounds has been evaluated and compared to that of VPA and valpromide (VPD). Valproic acid, and its two esteric derivatives were administered intravenously to six dogs at an equivalent dose (400 mg VPA) and their pharmacokinetics investigated. In the case of BDV, the biotransformation to VPA was complete, but in the case of GTV, it was only partial. Of the two investigated esteric prodrugs of VPA, only BDV demonstrated anticonvulsant activity and showed less neurotoxicity than VPA and VPD, and therefore had a better protective index. The anticonvulsant activity is explained on pharmacokinetic and pharmacodynamic grounds due to its complete conversion to VPA and the possible synergism in anticonvulsant activity between VPA and 1,4‐butanediol.
KW - Anticonvulsant activity
KW - Chemical delivery systems
KW - Pharmacokinetics
KW - Prodrugs
KW - Valproic acid
UR - http://www.scopus.com/inward/record.url?scp=0027507342&partnerID=8YFLogxK
U2 - 10.1002/bdd.2510140105
DO - 10.1002/bdd.2510140105
M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???
C2 - 8427944
AN - SCOPUS:0027507342
SN - 0142-2782
VL - 14
SP - 51
EP - 59
JO - Biopharmaceutics and Drug Disposition
JF - Biopharmaceutics and Drug Disposition
IS - 1
ER -