Disposition kinetics of hepp in rats after intravenous, oral, and intraperitoneal administration. Correlation of plasma and brain levels with the anticonvulsant effects

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 (VSS = 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 (EC50) 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 [Cserum = 109 e−0.25t, r2 = 0.95; Cbrain = 38 e2.53t + 91 e−0.21t, r2 = 0.93], with a Cbrain/Cplasma ratio of 1.1.