title: Pharmacokinetic-Pharmacodynamic Correlation and Brain Penetration of sec-Butylpropylacetamide, a New CNS Drug Possessing Unique Activity against Status Epilepticus.
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.
authors.affiliation: Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem , Jerusalem 91120, Israel.
authors.forename: Hafiz
authors.initials: H
authors.lastname: Mawasi
authors.affiliation: Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem , Jerusalem 91120, Israel.
authors.forename: David
authors.initials: D
authors.lastname: Bibi
authors.affiliation: Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem , Jerusalem 91120, Israel.
authors.forename: Tawfeeq
authors.initials: T
authors.lastname: Shekh-Ahmad
authors.affiliation: Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem , Jerusalem 91120, Israel.|Clinical Pharmacology Unit, Division of Medicine, Hadassah University Hospital , Jerusalem 91120, Israel.
authors.forename: Chanan
authors.initials: C
authors.lastname: Shaul
authors.affiliation: Clinical Pharmacology Unit, Division of Medicine, Hadassah University Hospital , Jerusalem 91120, Israel.
authors.forename: Simcha
authors.initials: S
authors.lastname: Blotnik
authors.affiliation: Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem , Jerusalem 91120, Israel.|David R. Bloom Center for Pharmacy, The Hebrew University of Jerusalem , Jerusalem 91120, Israel.
authors.forename: Meir
authors.initials: M
authors.lastname: Bialer
mesh_terms: D061605:Administration, Intravenous; D000577:Amides / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001569:Benzodiazepines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002491:Central Nervous System Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008401:Gas Chromatography-Mass Spectrometry; D007274:Injections, Intraperitoneal; D051381:Rats; D013226:Status Epilepticus / Q000188:drug therapy* / Q000378:metabolism*; D014635:Valproic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D000577:Amides; D000927:Anticonvulsants; D002491:Central Nervous System Agents; C570212:sec-butyl-propylacetamide; D001569:Benzodiazepines; D014635:Valproic Acid
keywords: benzodiazepine-resistant status epilepticus; new antiepileptic drugs; pharmacokinetic and pharmacodynamic analysis; various parenteral routes of administration