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

Abstract

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.

Disease-associated mutations in TRPM3 render the channel overactive via two distinct mechanisms

“…Given the increased constitutive activity of the mutants at body temperature, increased neuronal excitability and/or Ca 2+ -induced neuronal damage is a possible disease-causing mechanism. Primidone is a clinically approved antiepileptic drug; it is thought to exert its effects by being converted to barbiturate by the liver, but it crosses the blood brain barrier (Nagaki et al, 1999), and directly inhibits TRPM3 activity even below its therapeutic concentration (Krugel et al, 2017). Our data showing that primidone inhibited the basal activity of the mutant channels, suggests a potential therapy for this newly described channelopathy.…”

Pharmacotherapy of Essential Tremor

“…It is minimally bound to protein and penetrates the BBB well 104,105. Antitremorogenic effects of primidone can be observed at plasma levels that are much lower than those used for treatment of epilepsy 106.…”

Comparison of serum, cerebrospinal fluid and brain extracellular fluid pharmacokinetics of lamotrigine

“…In order to study CSF pharmacokinetics, direct sampling of CSF with simultaneous serum sampling has been successfully used ( Patsalos et al ., 1992 ; Semba et al ., 1993 ; Lolin et al ., 1994 ; Walker et al ., 1998 ; Doheny et al ., 1999 ; Nagaki et al ., 1999 ). The limited accessibility of CSF and the impracticability of repeated sampling in humans have meant that most of these drug studies have been carried out in animal models.…”