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 phenylethylmalonamide. As data on the inter-relationship between the systemic and central nervous system pharmacokinetics of primidone and its metabolites are sparse, we have investigated their temporal inter-relationship using a freely behaving rat model which allows repeated sampling of blood (100 microl) and cerebrospinal fluid (CSF; 20 microl). After administration, by intraperitoneal injection (50, 100 or 200 mg/kg), primidone rapidly appeared in both serum (Tmax mean range 1.5-2.5 h) and CSF (Tmax mean range 2.0-3.5 h), suggesting ready penetration of the blood-brain-barrier. This was also the case for phenylethylmalonamide and phenobarbital but peak concentration occurred later. Primidone, phenylethylmalonamide and phenobarbital concentrations rose linearly and dose-dependently in both serum and CSF. The mean free fraction (free/total concentration ratio) for primidone, phenylethylmalonamide and phenobarbital 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 similar to those of sera and essentially paralleled the pattern seen in sera.
Nagaki
S
S
Pharmacolgy and Therapeutics Unit, University Department of Clinical Neurology, Institute of Neurology, London, UK.
Ratnaraj
N
N
Patsalos
P N
PN
D000818:Animals; D006207:Half-Life; D008297:Male; D010634:Phenobarbital / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D010657:Phenylethylmalonamide / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D011324:Primidone / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
D011324:Primidone; D010657:Phenylethylmalonamide; D010634:Phenobarbital