Blood and cerebrospinal fluid pharmacokinetics of primidone and its primary pharmacologically active metabolites, phenobarbital and phenylethylmalonamide in the rat

Primidone is a clinically useful antiepileptic drug that is metabolised to two pharmacologically active metabolites phenobarbital and phenylethylmalon amide. As data on the inter-relationship between the systemic and central n ervous system pharmacokinetics of primidone and its metabolites are sparse, we have investigated their temporal inter-relationship using a freely beha ving rat model which allows repeated sampling of blood (100 mu l) and cereb rospinal fluid (CSF; 20 mu l). After administration, by intraperitoneal inj ection (50, 100 or 200 mg/kg), primidone rapidly appeared in both serum (T- max mean range 1.5-2.5 h) and CSF (T-max mean range 2.0-3.5 h), suggesting ready penetration of the blood-brain-barrier This was also the case for phe nylethylmalonamide and phenobarbital but peak concentration occurred later. Primidone, phenylethylmalonamide and phenobarbital concentrations rose lin early and dose-dependently in both serum and CSF. The mean free fraction (f ree/total concentration ratio) for primidone, phenylethylmalonamide and phe nobarbital was 0.86, 0.97 and 0.88, respectively, and, as their respective mean CSF/serum ratio values were 0.73, 1.06 and 0.65, it would suggest that equilibration between the blood and CSF compartments is rapid. CSF mean t( 1/2) values for primidone, phenylethylmalonamide and phenobarbital were sim ilar to those of sera and essentially paralleled the pattern seen in sera.