BIOAVAILABILITY AND ANTICONVULSANT ACTIVITY OF 2-CYANOGUANIDINOPHENYTOIN, A STRUCTURAL ANALOG OF PHENYTOIN

Phenytoin is extensively used in Europe and the United States for the treatment of generalized tonic clonic seizures (grand mal). However, t he efficacy is lowered by the erratic bioavailability after oral admin istration. The current study was conducted in order to investigate the physicochemical properties, the bioavailability, and the anticonvulsa nt activity of cyanoguanidinophenytoin (CNG-DPH), a structural analogu e of phenytoin, which was obtained by the replacement of the urea moie ty by a cyanoguanidine moiety. CNG-DPH was prepared under homogeneous Blitz conditions and under heterogeneous phase-transfer conditions. CN G-DPH is poorly water soluble and has a pK(a) of 5.3. At pH 7.4, log P ' was 1.16, from which a pH-independent log P of 3 can be calculated. Pharmacokinetic parameters were obtained after oral administration of CNG-DPH to rats and were compared to those of phenytoin after administ ration of an equimolar amount. AUC, t(max), and C-max were significant ly increased compared to those of phenytoin. The anticonvulsant profil e was similar to the profile of phenytoin. CNG-DPH was active in the m aximal electroshock seizure test, albeit 7-fold less active than pheny toin. The analogue did not protect animals against convulsions induced by chemicals such as pentylenetetrazole, picrotoxin, N-methyl-asparta te, strychnine, and bicuculline. It is concluded that while the bioiso steric exchange of the urea moiety of the molecule with the cyanoguani dine moiety dramatically changed the physicochemical and pharmacokinet ic parameters compared to those of phenytoin, the concomitant change o f the affinity toward molecular targets reduced the pharmacological ac tivity and the therapeutic efficacy of the compound.