PHARMACOKINETICS OF THE NOVEL ANTICONVULSANT HEPP AFTER SINGLE INTRAVENOUS ADMINISTRATION OF 3 DIFFERENT DOSES IN DOGS

HEPP (D, L-3-hydroxy-3-ethyl-3-phenylpropanamide) is a novel compound with a wide spectrum of anticonvulsant activity and relatively low tox icity. The aim of this investigation was to study the pharmacokinetics of HEPP in mongrel dogs and to assess its linearity after intravenous administration of 8, 15, and 30 mg kg(-1). A biphasic disappearance p attern with a rapid distribution phase was observed in the plasma conc entration versus time curve. The mean terminal half-life (t(1/2 beta)) was the same after the three doses (3. 4 +/- 0. 15 h) and the mean ha lf-lives of the distribution phase (t(1/2 alpha)) were not significant ly different after the three doses (0.09 +/- 0.02, 0.08 +/- 0.07, and 0.11 +/- 0.03 h for 8, 15, and 30 mg kg(-1) respectively). The mean AU C(0-infinity), values were 44.1 +/- 10.8, 72.1 +/- 8.8, and 127.4 +/- 23.2 mu g h mL(-1), respectively, showing a linear increase. The indiv idual values of AUC(0-infinity), corrected for the administered dose ( AUC(0-infinity)/D) were 0.29 +/- 0.04, 0.23 +/- 0.05, and 0.22 +/- 0.0 6 h mL(-1). These values were not statistically different. Neither the mean residence time (MRT = 4.55 +/- 1.50, 4.90 +/- 1.32, and 5.07 +/- 1.95 h), the steady state volume of distribution (V-ss = 0.86 +/- 0.1 1, 1.01 +/- 0.17, and 1.20 +/- 0.40 L kg(-1)) nor the systemic clearan ce (Cl = 3.36 +/- 0.82, 3.53 +/- 0.44, and 4.02 +/- 0.68 mL min(-1) kg (-1)) showed significant differences between doses. The values of V-ss suggest that HEPP is distributed in the whole body fluid. The invaria nt pharmacokinetic parameters and the direct correlation between AUC(0 -infinity), and the dose suggest that the kinetics of HEPP in dogs are linear over the range of doses studied.