ANTICONVULSANT ACTIVITY, TERATOGENICITY AND PHARMACOKINETICS OF NOVEL VALPROYLTAURINE DERIVATIVES
Abstract number :
2.175
Submission category :
Year :
2002
Submission ID :
3424
Source :
www.aesnet.org
Presentation date :
12/7/2002 12:00:00 AM
Published date :
Dec 1, 2002, 06:00 AM
Authors :
Nina Isoherranen, Ofer Spiegelstein, Boris Yagen, Richard H. Finnell, Jose H. Woodhead, H. Steve White, Bogdan Wlodarczyk, Meir Bialer. Department of Pharmaceutics, Faculty of Medicine Hebrew University, Jerusalem, Israel; Center for Environmental and Gen
RATIONALE: The objective of this study was to evaluate the structure-pharmacokinetic pharmacodynamic relationships in the anticonvulsant activity and teratogenicity of novel taurine derivatives of valproic acid (VPA).
METHODS: The following four new taurine derivatives of VPA were synthesized and their anticonvulsant activity was evaluated in the Frings audiogenic seizure (AGS) susceptible mice; valproyltaurine (VTA), valproyltaurinamide (VTD), N,N-dimethyl-valproyltaurineamide (DM-VTD) and N-isopropyl valproyltaurinamide (I-VTD). The ability of VTD, VTA, DM-VTD and I-VTD to induce gross malformations was assessed following ip administration (600mg/kg) of test compounds in SWV/Fnn mice, an inbred strain that is highly susceptible to antiepileptic drug induced teratogenicity.
The pharmacokinetics of the above compounds was also assessed in SWV/Fnn mice following ip administration (300 mg/kg). Plasma and brain concentrations were analysed using a gas chromatographic assay.
RESULTS: In the Frings AGS-susceptible mouse, VTD was 2-3 times more potent than I-VTD and DM-VTD following ip administration (ED50[ssquote]s:51, 126 and 154 mg/kg, respectively). In contrast, VTA was inactive in this model.
In SWV/Fnn mice, VTA and VTD did not induce any congenital malformations in liveborn fetuses, however VTD treatment resulted in a significantly higher rate of resorptions (25%) compared to control animals (4%). DM-VTD was found to be highly embryotoxic causing 35% resorptions, and excencephaly in 17% of liveborn fetuses. Treatment with I-VTD caused 22% resorptions and induced malformations in 7% of the exposed liveborn fetuses. In comparison, VPA induced exencephaly in 82% of exposed embryos and caused 20% resorptions under similar experimental conditions.
Following ip administration to SWV mice, DM-VTD was metabolized by N-demethylations to N-methyl valproyltaurinamide and subsequently to VTD. Similarly, I-VTD was N-dealkylated to VTD. The obtained pharmacokientic parameters are presented in the table below.
CONCLUSIONS: Of the valproyltaurine derivatives evaluated, VTD displayed the highest anticonvulsant potency, a good protective index, lack of induction of neural tube defects and favorable pharmacokinetics. The results presented here support the continued evaluation of VTD as a novel investigational antiepileptic drug.[table1]
[Supported by: This study was supported by the NIH grant NO1-NS-4-2311 and the Horowitz Fund, Jerusalem, Israel.]