Pharmacokinetics of phenobarbital and propylhexedrine after administration of barbexaclone in the mouse

Summary

The antiepileptic barbexaclone is the salt of the base propylhexedrine (indirect sympathomimetic) and phenylethylbarbituric acid. After i.v. and oral administration of 66 mg/kg barbexaclone to mice the time course of propylhexedrine and phenobarbital concentrations was studied in plasma, brain, lung, liver, kidney, spleen, heart, and skeletal muscle. Furthermore, the kinetics of phenobarbital were studied after treatment with an equimolar dose of phenobarbital-Na (40 mg/kg).

In contrast to the i.v. bolus of phenobarbital-Na, barbexaclone was non-lethal only when infused over a period of 3 min. After the i.v. administration of either salt, phenobarbital plasma levels declined monoexponentially with a half-life of 7.5 h; the volume of distribution was 0.78l/kg. After oral application absorption of phenobarbital was complete with both salts, though it was delayed after barbexaclone. The latter was the result of a delayed gastro-intestinal passage. Brain uptake of phenobarbital was a slow process, equilibrium with plasma concentrations being reached only 30 min after injection. Propylhexedrine reduced phenobarbital concentrations in brain as evident from steady state tissue-plasma ratios. This was observed after i.v. as well as after oral application.

After i.v. application of barbexaclone the following pharmacokinetic parameters for propylhexedrine were determined: t _0.5α 0.31 h, t _0.5β 2.5h, Vd_β 19.3l/kg; bioavailability (AUC oral/AUC i.v.) 0.37. Propylhexedrine penetrated the blood-brain barrier rapidly. High but unequal tissue accumulation was observed: lung=kidney>liver=brain>spleen >heart>skeletal muscle.