Disposition kinetics of HEPP in rats after intravenous, oral, and intraperitoneal administration. Correlation of plasma and brain levels with the anticonvulsant effect.
D, L-3-hydroxy-3-ethyl-3-phenylpropanamide (HEPP) is a synthetic drug with anticonvulsant effects in a variety of seizure models. HEPP pharmacokinetics was studied after single 50 mg kg-1 intravenous (i.v.), intraperitoneal (i.p.), 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 (beta = 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 (3.30 mL 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) micrograms mL-1 in serum and 60.1 (55.4-65.1) micrograms 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-0.25t, r2 = 0.95; C(brain) = 38 e-2.53t + 91 e-0.21t, r2 = 0.93], with a C(brain)/C(plasma) ratio of 1.1.
Gómez
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LE
Departamento de Farmacología y Toxicología, Instituto Politécnico Nacional, México City, México.
Cueva-Rolón
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Lehmann
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PA
D000284:Administration, Oral; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001798:Blood Proteins / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D008297:Male; D010666:Phenylpropionates / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000188:drug therapy / Q000378:metabolism
D000927:Anticonvulsants; D001798:Blood Proteins; D010666:Phenylpropionates; C067697:beta-hydroxy-beta-ethyl-phenylpropionamide