PMID- 12812999
OWN - NLM
STAT- MEDLINE
DCOM- 20040324
LR  - 20240315
IS  - 0007-1188 (Print)
IS  - 0007-1188 (Linking)
VI  - 139
IP  - 4
DP  - 2003 Jun
TI  - Anticonvulsant activity, teratogenicity and pharmacokinetics of novel 
      valproyltaurinamide derivatives in mice.
PG  - 755-64
AB  - 1 The purpose of this study was to synthesize novel valproyltaurine (VTA) 
      derivatives including valproyltaurinamide (VTD), N-methyl-valproyltaurinamide 
      (M-VTD), N,N-dimethyl-valproyltaurinamide (DM-VTD) and 
      N-isopropyl-valproyltaurinamide (I-VTD) and evaluate their 
      structure-pharmacokinetic-pharmacodynamic relationships with respect to 
      anticonvulsant activity and teratogenic potential. However, their hepatotoxic 
      potential could not be evaluated. The metabolism and pharmacokinetics of these 
      derivatives in mice were also studied. 2 VTA lacked anticonvulsant activity, but 
      VTD, DM-VTD and I-VTD possessed anticonvulsant activity in the Frings audiogenic 
      seizure susceptible mice (ED(50) values of 52, 134 and 126 mg kg(-1), 
      respectively). 3 VTA did not have any adverse effect on the reproductive outcome 
      in the Swiss Vancouver/Fnn mice following a single i.p. injection of 600 mg 
      kg(-1) on gestational day (GD) 8.5. VTD (600 mg kg(-1) at GD 8.5) produced an 
      increase in embryolethality, but unlike valproic acid, it did not induce 
      congenital malformations. DM-VTD and I-VTD (600 mg kg(-1) at GD 8.5) produced a 
      significant increase in the incidence of gross malformations. The incidence of 
      birth defects increased when the length of the alkyl substituent or the degree of 
      N-alkylation increased. 4 In mice, N-alkylated VTDs underwent metabolic 
      N-dealkylation to VTD. DM-VTD was first biotransformed to M-VTD and subsequently 
      to VTD. I-VTD's fraction metabolized to VTD was 29%. The observed metabolic 
      pathways suggest that active metabolites may contribute to the anticonvulsant 
      activity of the N-alkylated VTDs and reactive intermediates may be formed during 
      their metabolism. In mice, VTD had five to 10 times lower clearance (CL), and 
      three times longer half-life than I-VTD and DM-VTD, making it a more attractive 
      compound than DM-VTD and I-VTD for further development. VTD's extent of brain 
      penetration was only half that observed for the N-alkylated taurinamides 
      suggesting that it has a higher intrinsic activity that DM-VTD and I-VTD. 5 In 
      conclusion, from this series of compounds, although VTD caused embryolethality, 
      this compound emerged as the most promising new antiepileptic drug, having a 
      preclinical spectrum characterized by the highest anticonvulsant potential, 
      lowest potential for teratogenicity and favorable pharmacokinetics.
FAU - Isoherranen, Nina
AU  - Isoherranen N
AD  - Department of Pharmaceutics, School of Pharmacy, Hebrew University of Jerusalem, 
      Israel.
FAU - Yagen, Boris
AU  - Yagen B
FAU - Spiegelstein, Ofer
AU  - Spiegelstein O
FAU - Finnell, Richard H
AU  - Finnell RH
FAU - Merriweather, Michelle
AU  - Merriweather M
FAU - Woodhead, Jose H
AU  - Woodhead JH
FAU - Wlodarczyk, Bogdan
AU  - Wlodarczyk B
FAU - White, H Steve
AU  - White HS
FAU - Bialer, Meir
AU  - Bialer M
LA  - eng
PT  - Journal Article
PL  - England
TA  - Br J Pharmacol
JT  - British journal of pharmacology
JID - 7502536
RN  - 0 (Anticonvulsants)
RN  - 0 (Teratogens)
RN  - 614OI1Z5WI (Valproic Acid)
SB  - IM
MH  - Animals
MH  - Anticonvulsants/*adverse effects/chemical synthesis/*pharmacokinetics
MH  - Dose-Response Relationship, Drug
MH  - Drug Evaluation, Preclinical
MH  - Embryonic and Fetal Development/drug effects
MH  - Injections, Intraperitoneal
MH  - Mice
MH  - Mice, Mutant Strains
MH  - Molecular Structure
MH  - Seizures/drug therapy
MH  - Teratogens/pharmacokinetics/*toxicity
MH  - Valproic Acid/chemical synthesis/*pharmacokinetics/therapeutic use
PMC - PMC1573897
EDAT- 2003/06/19 05:00
MHDA- 2004/03/25 05:00
PMCR- 2004/06/01
CRDT- 2003/06/19 05:00
PHST- 2003/06/19 05:00 [pubmed]
PHST- 2004/03/25 05:00 [medline]
PHST- 2003/06/19 05:00 [entrez]
PHST- 2004/06/01 00:00 [pmc-release]
AID - 0705301 [pii]
AID - 10.1038/sj.bjp.0705301 [doi]
PST - ppublish
SO  - Br J Pharmacol. 2003 Jun;139(4):755-64. doi: 10.1038/sj.bjp.0705301.