Anticonvulsant activity, teratogenicity and pharmacokinetics of novel valproyltaurinamide derivatives in mice.
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.
Isoherranen
Nina
N
Department of Pharmaceutics, School of Pharmacy, Hebrew University of Jerusalem, Israel.
Yagen
Boris
B
Spiegelstein
Ofer
O
Finnell
Richard H
RH
Merriweather
Michelle
M
Woodhead
Jose H
JH
Wlodarczyk
Bogdan
B
White
H Steve
HS
Bialer
Meir
M
D000818:Animals; D000927:Anticonvulsants / Q000009:adverse effects* / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005314:Embryonic and Fetal Development / Q000187:drug effects; D007274:Injections, Intraperitoneal; D051379:Mice; D008817:Mice, Mutant Strains; D015394:Molecular Structure; D012640:Seizures / Q000188:drug therapy; D013723:Teratogens / Q000493:pharmacokinetics / Q000633:toxicity*; D014635:Valproic Acid / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000627:therapeutic use
D000927:Anticonvulsants; D013723:Teratogens; D014635:Valproic Acid