Pharmacokinetic-pharmacodynamic correlation and brain penetration of sec-butylpropylacetamide, a new CNS drug possessing unique activity against status epilepticus

Hafiz Mawasi, David Bibi, Tawfeeq Shekh-Ahmad, Chanan Shaul, Simcha Blotnik, Meir Bialer

Research output: Contribution to journalArticlepeer-review

Abstract

sec-Butylpropylacetamide (SPD) is the amide derivative of valproic acid (VPA). SPD possess a wide-spectrum anticonvulsant profile better than that of VPA and blocks status epilepticus (SE) induced by pilocarpine and organophosphates. The activity of SPD on SE is better than that of benzodiazepines (BZDs) in terms of the ability to block SE when given 20-60 min after the beginning of a seizure. However, intraperitoneal (i.p.) administration to rats cannot be extrapolated to humans. Consequently, in the current study a comparative pharmacokinetic (PK)-pharmacodynamic analysis of SPD was conducted following i.p., intramuscular (i.m.), and intravenous (i.v.) administrations to rats. SPD brain and plasma levels were quantified at various times after dosing following i.p. (60 mg/kg), i.v. (60 mg/kg), and i.m. administrations (120 mg/kg) to rats, and the major PK parameters of SPD were estimated. The antiseizure (SE) efficacies of SPD and its individual stereoisomers were assessed in the pilocarpine-induced BZD-resistant SE model following i.p. and i.m. administrations to rats at 30 min after seizure onset. The absolute bioavailabilities of SPD following i.p. and i.m. administrations were 76% (i.p.) and 96% (i.p.), and its clearance and half-life were 1.8-1.5 L h-1 kg-1 and 0.5-1.7 h, respectively. The SPD brain-to-plasma AUC ratios were 1.86 (i.v.), 2.31 (i.p.), and 0.77 (i.m.). Nevertheless, the ED50 values of SPD and its individual stereoisomers were almost identical in the rat pilocarpine-induced SE model following i.p. and i.m. administrations. In conclusion, in rats SPD is completely or almost completely absorbed after i.m. and i.p. administration and readily penetrates into the brain. Consequently, in spite of PK differences, the activities of SPD in the BZD-resistant SE model following i.m. and i.p. administrations are similar.

Original languageEnglish
Pages (from-to)2492-2496
Number of pages5
JournalMolecular Pharmaceutics
Volume13
Issue number7
DOIs
StatePublished - 5 Jul 2016

Keywords

  • benzodiazepine-resistant status epilepticus
  • new antiepileptic drugs
  • pharmacokinetic and pharmacodynamic analysis
  • various parenteral routes of administration

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

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