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Titolo:
BIOAVAILABILITY AND ANTICONVULSANT ACTIVITY OF 2-CYANOGUANIDINOPHENYTOIN, A STRUCTURAL ANALOG OF PHENYTOIN
Autore:
LAMBERT DM; MASEREEL B; GALLEZ B; GEURTS M; SCRIBA GKE;
Indirizzi:
CATHOLIC UNIV LEUVEN,DEPT PHARMACEUT SCI,LAB PHARMACEUT CHEM,CMFA 7340,AVE E MOUNIER B-1200 BRUSSELS BELGIUM UNIV LIEGE,INST PHARM,LAB PHARMACEUT CHEM B-4000 LIEGE BELGIUM UNIV MUNSTER,DEPT PHARMACEUT CHEM D-48149 MUNSTER GERMANY
Titolo Testata:
Journal of pharmaceutical sciences
fascicolo: 10, volume: 85, anno: 1996,
pagine: 1077 - 1081
SICI:
0022-3549(1996)85:10<1077:BAAAO2>2.0.ZU;2-F
Fonte:
ISI
Lingua:
ENG
Soggetto:
DELIVERY SYSTEMS; DRUGS; PRODRUGS; SOLUBILITY;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
32
Recensione:
Indirizzi per estratti:
Citazione:
D.M. Lambert et al., "BIOAVAILABILITY AND ANTICONVULSANT ACTIVITY OF 2-CYANOGUANIDINOPHENYTOIN, A STRUCTURAL ANALOG OF PHENYTOIN", Journal of pharmaceutical sciences, 85(10), 1996, pp. 1077-1081

Abstract

Phenytoin is extensively used in Europe and the United States for thetreatment of generalized tonic clonic seizures (grand mal). However, the efficacy is lowered by the erratic bioavailability after oral administration. The current study was conducted in order to investigate the physicochemical properties, the bioavailability, and the anticonvulsant activity of cyanoguanidinophenytoin (CNG-DPH), a structural analogue of phenytoin, which was obtained by the replacement of the urea moiety by a cyanoguanidine moiety. CNG-DPH was prepared under homogeneousBlitz conditions and under heterogeneous phase-transfer conditions. CNG-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 ofCNG-DPH to rats and were compared to those of phenytoin after administration of an equimolar amount. AUC, t(max), and C-max were significantly increased compared to those of phenytoin. The anticonvulsant profile was similar to the profile of phenytoin. CNG-DPH was active in the maximal electroshock seizure test, albeit 7-fold less active than phenytoin. The analogue did not protect animals against convulsions induced by chemicals such as pentylenetetrazole, picrotoxin, N-methyl-aspartate, strychnine, and bicuculline. It is concluded that while the bioisosteric exchange of the urea moiety of the molecule with the cyanoguanidine moiety dramatically changed the physicochemical and pharmacokinetic parameters compared to those of phenytoin, the concomitant change of the affinity toward molecular targets reduced the pharmacological activity and the therapeutic efficacy of the compound.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 08/07/20 alle ore 06:58:16