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

Abstract

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.

Functional evaluation of polymorphisms in the human ABCB1 gene and the impact on clinical responses of antiepileptic drugs

“…It seems unlikely that the weak inhibition of Pgp was of clinical relevance in the monotherapy with AEDs, even when considering the fact that phenytoin, carbamazepine and lamotrigine may accumulate in the human brain by a factor of 1.2-2.8 [64,65]. This study, however, did not exclude the possibility that inhibition may be potentiated in the addon therapies when two AEDs with Pgp substrate and inhibitor characteristics were given in combination.…”

Therapeutic Index Estimation of Antiepileptic Drugs: A Systematic Literature Review Approach

“…31,53–57 In addition, it has been reported that some subjects have remained seizure-free at phenobarbital levels well below 10 μg/mL, 52 while clearly other subjects can have seizures refractory to phenobarbital therapy despite levels in the therapeutic range. 58 …”

Interactions of the Anticonvulsants Diphenylhydantoin and Carbamazepine with Adenosine on Cerebral Cortical Neurons

“…DPH concentrations in the plasma of epileptic patients range from 10 to 25 p,g/ml(50-100 pM), with a braidplasma concentration ratio of about 1 * 2:1 (Jones et al, 1983). Cerebrospinal fluid from such patients contains about 4-8 p M of DPH (Sironi et al, 1980). After an intravenous injection of 10 mg/ kg (the dose level used in the present study), DPH achieves a concentration of 40-60 pg/g (160-240 pmol/kg) in the cat brain at a time when the plasma concentration is approximately 20 pg/ml (80 pM) (Ramsey et al, 1979).…”