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Disposition kinetics of hepp in rats after intravenous, oral, and intraperitoneal administration. Correlation of plasma and brain levels with the anticonvulsant effects
Author(s) -
Gómez Lisbeth E.,
CuevaRolón Rafael,
Lehmann F. Pedro A.
Publication year - 1995
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.2510160203
Subject(s) - anticonvulsant , disposition , pharmacokinetics , pharmacology , oral administration , kinetics , plasma concentration , medicine , chemistry , epilepsy , psychology , psychiatry , social psychology , physics , quantum mechanics
Abstract D, L‐3‐hydroxy‐3‐ethyl‐3‐phenylpropanamide (HEPP) is a synthetic drug with anticovulsant effects in a variety of seizure models. HEPP pharmacokinetics was studied after single 50 mg kg −1 intravenous (IV), intraperitoneal (IP), and oral (PO) administration in male albino Wistar rats. The plasma concentration against time curves showed a biphasic decay pattern with a similar distribution phase and the same terminal rate constant (β = 0.22 h −1 ) by all three routes. The apparent volume of distribution at steady state ( V SS = 0.80 L kg −1 ) indicates that HEPP is extensively distributed in extracellular tissues. This finding agrees very well with its low binding to plasma protein (mean bound fraction = 19.3 ± 1.1%). The systemic clearance (Cl) was very low (3.30mL min −1 kg −1 ). The bioavailability after IP and PO administration was 0.80 and 0.60 respectively. In the pharmacokinetic‐pharmacodynamic studies a direct relationship was found between the protective effect of HEPP against pentylenetetrazole (PTZ) induced seizures and its concentration in plasma and/or brain. The concentrations at half‐maximal effect (EC 50 ) with 95% confidence interval (Cl) were 70.6 (66–75.5) μg mL −1 in serum and 60.1 (55.4–65.1) μg g −1 in brain. There was a rapid uptake of HEPP into the brain, and after the distributive phase, the disappearances in plasma and brain were almost parallel [ C serum = 109 e −0.25 t , r 2 = 0.95; C brain = 38 e 2.53 t + 91 e −0.21 t , r 2 = 0.93], with a C brain / C plasma ratio of 1.1.