Pharmacokinetic and pharmacodynamic analysis of (E)-2-ene valproyl derivatives of glycine and valproyl derivatives of nipecotic acid

Meir Bialer*, Bashier Kadry, Ali Abdul-Hai, Abdullah Haj-Yehia, Jeff Sterling, Yaacov Herzig, Mitchel Shirvan

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

GABA is a major inhibitory neurotransmitter in mammals, whose uptake in glial cells is inhibited by nipecotic acid. In addition to GABA, glycine is an important inhibitory neurotransmitter. Valproic acid (VPA) is one of the four established antiepileptics and (E)-2-ene valproic acid ((E)-2-ene VPA) is its major active metabolite. The described structure-pharmacokinetic-pharmacodynamic relationship (SPPR) study explored the possibility of utilizing valproyl derivatives of glycine and nipecotic acid as new antiepileptics. The pharmacokinetics and pharmacodynamics (anticonvulsant activity and neurotoxicity) of the following conjugation products were investigated: (E)-2-ene valproyl glycinamide (between (E)-2-ene VPA and glycinamide) and valproyl nipecotic acid and valproyl nipecotamide (between VPA and nipecotic acid). Out of the investigated compounds only (E)-2-ene valproyl glycinamide showed a good anticonvulsant profile in both mice and rats due to its better pharmacokinetic and pharmacodynamic profile. (E)-2-ene valproyl glycinamide was more potent than VPA and showed an activity and a safety margin similar to those of its analogous compound valproyl glycinamide. The investigated valproyl derivatives did not operate as chemical drug delivery systems (CDDSs) of glycine or nipecotic acid, but, rather, acted as drugs on their own. (E)-2-ene valproyl glycinamide was partially excreted unchanged in the urine (f(e) = 7.4%), while its urinary metabolite was (E)-2-ene valproyl glycine. Unlike the new antiepileptic tiagabine, in which nipecotic acid is attached to 4,4-di-(3-methylthien-2-yl)-3-butenyl and yields an active compound, the conjugation between nipecotic acid or its amide and VPA yielded inactive entities. In contrast to nipecotic acid, the conjugation between VPA or (E)-2-ene VPA and glycinamide gave two active compounds with similar pharmacokinetic and pharmacodynamic profiles.

Original languageEnglish
Pages (from-to)565-575
Number of pages11
JournalBiopharmaceutics and Drug Disposition
Volume17
Issue number7
DOIs
StatePublished - Oct 1996

Keywords

  • (E)-2-ene valproyl glycinamide
  • Anticonvulsant activity
  • Structure-pharmacokinetic-pharmacodynamic relationships (SPPR)
  • Valproyl nipecotamide
  • Valproyl nipecotic acid

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