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Preclinical evaluation of the pharmacokinetics, brain uptake and metabolism of E121, an antiepileptic enaminone ester, in rats
Author(s) -
Khurana Manoj,
Salama Noha N.,
Scott Kenneth R.,
Nemieboka Noble N.,
Bauer Kenneth S.,
Eddington Natalie D.
Publication year - 2003
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/bdd.376
Subject(s) - pharmacokinetics , anticonvulsant , metabolite , cmax , chemistry , pharmacology , metabolism , urine , in vivo , ed50 , excretion , epilepsy , biochemistry , medicine , biology , in vitro , microbiology and biotechnology , psychiatry
The present study describes the brain uptake, pharmacokinetics and metabolism of an anticonvulsant enaminone ester E121, which belongs to a new and active series of compounds with potential in vivo anticonvulsant activity in rodent models, in rats. A single dose of E121 was administered i.p. to male Sprague Dawley rats at 10 mg E121/kg body weight. Cohorts of animals ( n =3) were killed at varying times over 0–24 h to collect plasma and brain samples. Urinary excretion of E121 was studied in a separate group of five rats at the same dose. A validated HPLC method was used to quantify E121 and its metabolites in plasma, brain and urine. LC‐MS/MS was used to characterize the metabolites. The plasma and brain C max of 11.0±3.0 mg/l and 10.4±1.4 mg/kg, respectively, were observed for E121 at 15 min post dose and they declined in a mono‐exponential fashion. The plasma Cl / F and t 1/2 were 0.57 l/h/kg and 0.75 h, respectively. The brain uptake ratio of E121 was 0.9. Mass spectral analysis of urine showed two major metabolites ( m / z 280) and one minor metabolite ( m / z 236) that were consistent with initial hydrolysis of the compound to the acid followed by further decarboxylation and appears to be the major route of elimination of E121. The rapid and moderate brain uptake of E121 correlates well with its potential anticonvulsant activity (ED 50 3.0 mg/kg p.o. in rats). The brain uptake, pharmacokinetic and metabolic profile of E121 supports the need to further evaluate this compound for its potential as an antiepileptic. Copyright © 2003 John Wiley & Sons, Ltd.