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.

Drogas anticonvulsivantes en suero y líquido cefalorraquideo de pacientes epilépticos: cuantificación por cromatografía líquida / Anticonvulsant drugs in serum and crebrospinal fluid of epileptical patients: liquid chromatography measurement

Se desarrolló un procedimiento de cromatografía líquida de alta presión para cuantificar simultáneamente varias drogas anticonvulsivantes en el suero y líquido cefalorraquídeo de 20 pacientes. Los coeficientes de correlación para las concentraciones en ambos líquidos decarbamazepina, fenobarbital y fenitoína fueron r=0,8588 (p<0,01), r=0,9721 (p<0,01) y r=0,9289 (p<0,01), respectivamente. Las concentraciones de cada droga en líquido cefalorraquídeo representaron porcentajes de la concentración en suero, comparables a los referidos en la literatura. Las concentraciones séricas de carbamazepina en los pacientes sin barbitúricos asociados fueron mayores que las de aquellos bajo politerapia con barbitúricos, independientemente de la dosis. La fenitoína y las concentraciones de fenobarbital en suero y líquido cefalorraquídeo. Estos resultados aqpoyan el uso de la monoterapia para tratar las epilepsias

Diphenylhydantoin and primidone in tears.

Diphenylhydantoin (PHT) and primidone (PRM) were determined by the EMIT technique in the plasma, tears, saliva, and CSF of epileptic patients. Results indicate for PHT that tear values are more strictly correlated than are the saliva values to plasma and CSF concentrations. As for PRM, the data obtained show great interindividual variability of concentration in the different body fluids--in agreement with the wide range of both protein binding and half-life of this drug.

Antiepileptic drug distribution in cerebral cortex, ammon's horn, and amygdala in man.

Significant correlations in the concentrations of phenobarbital, phenytoin, and carbamazepine in the brain, plasma, and cerebrospinal fluid were found in 12 surgically treated epileptic patients. These findings confirm the clinical reliability of monitoring anticonvulsant drug plasma levels as part of the routine management of epilepsy. Phenobarbital, phenytoin, and carbamazepine are uniformly distributed in the gray and white matter in different brain areas (except for a higher concentration of phenobarbital in the rhinencephalic structures in comparison with the corresponding temporal neocortex) and in normal and scar tissue. In these 12 patients, all of whom were medically resistant, molar cortex concentration of phenobarbital and phenytoin was at "therapeutic" levels or even higher. These data suggest that in therapy-resistant patients, despite cerebral drug concentrations of the same therapeutic level as, or higher than, those present in medically controlled patients, anticonvulsant drugs are pharmacologically ineffective.

Diphenylhydantoin, phenobarbital, and primidone in saliva, plasma, and cerebrospinal fluid.

Diphenylhydantoin, primidone, and phenobarbital were determined in saliva and plasma of 164 patients by gas-liquid chromatography. The saliva ratio was about one-tenth in patients on diphenylhydantoin, 0.32-0.38 on phenobarbital alone and with other drugs, 0.97 and 0.96 on primidone alone and with other drugs. The S/P ratio of phenobarbital was similar in patients treated with primidone alone or with co-medication. For diphenylhydantoin and primidone, the S/P and CSF/plasma ratio were similar; for phenobarbital the S/P ratio was lower due to the difference in pH of saliva and CSF. Thus the concentration in saliva serves as a measure of the nonprotein-bound or free concentration in plasma with the advantage that saliva is easy to obtain. Co-medication does not change the S/P ratio for the three drugs studied. The high correlation between levels in plasma and in saliva allows the plasma levels to be predicted from the concentration in saliva.

Brain concentrations of phenytoin, phenobarbitone and primidone in epileptic patients.

Plasma, brain, lumbar CSF, skeletal muscle, skin and bone concentrations of phenytoin, phenobarbitone and primidone have been measured in specimens from patients undergoing temporal lobectomy for chronic epilepsy. A good correlation was found between the plasma and brain concentrations of each drug. Similarly, a good correlation was found between the plasma and CSF concentrations of each drug. Assuming that CSF is an ultrafiltrate of plasma, the percentage of phenytoin, phenobarbitone and primidone which was unbound in plasma was 10-14%, 43% and 81% respectively. Skeletal muscle concentrations of phenytoin and phenobarbitone and the skin concentration of phenytoin, also correlated with the plasma concentrations, but the remaining tissues did not give significant correlations.

Anticonvulsant level in saliva, serum, and cerebrospinal fluid.

Levels of four anticonvulsant drugs were measured simultaneously in saliva, spinal fluid, and dialyzed serum, i.e., free drug in serum. The level of diphenylhydantoin and possibly of carbamazepine was the same in the three body fluids. The leves of phenobarbital was the same in spinal fluid and dialyzed serum, but was lower in saliva. The level of primidone was different in each body fluid. The technique is simple (flow of saliva stimulated when the subject chews candle was or Teflon) and will be useful to determine the level of free diphenylhydantoin and carbamazepine, which is more closely related to intoxication or drug failure than is the total level of drug.