Possible Interaction: Gamma-Aminobutyric Acid and Phenytoin

“Brain GABA levels were below normal in four of nine patients taking carbamazepine or phenytoin and one of five taking valproate.”

“Serum concentrations of phenytoin were lower during gamma-vinyl GABA treatment than during placebo (p less than 0.05), but the concentrations of other anticonvulsants given concomitantly did not change.”

“In cortical neuron recordings, the current induced by 1 microM GABA was enhanced by carbamazepine and phenytoin with EC50 values of 24.5 nM and 19.6 nM and maximal potentiations of 45.6% and 90%, respectively.”

“We report here that carbamazepine and phenytoin , two widely used antiepileptic drugs, potentiate gamma-aminobutyric acid (GABA)-induced Cl- currents in human embryonic kidney cells transiently expressing the alpha 1 beta 2 gamma 2 subtype of the GABAA receptor and in cultured rat cortical neurons.”

“ Phenytoin exerts important effects on neuronal sodium and calcium ion transport, reduces repetitive firing, reduces excitation in neuronal networks of the brainstem reticular formation, and produces some decrease in the effect of the inhibitory transmitter, γ-aminobutyric acid (GABA).”

“The mechanism underlying this ophthalmoplegia may be related to the ability of phenytoin to potentiate inhibitory synapses in the vestibulo-oculomotor pathway which utilize gamma aminobutyric acid , and to increase the discharge rate of Purkinje cells which exert an inhibitory influence on the same structures.”

“ Phenytoin modulated the expression of genes which may affect neurotransmission, e.g. glutamate decarboxylase 1 (Gad1) and γ-aminobutyric acid A receptor , alpha 5 (Gabra5).”

“Supratherapeutic doses of AZM, CBZ, PHT , TPM, and ZNS decreased extracellular levels of GABA , NE, DA, and 5-HT, without affecting Glu levels.”

“Phenobarbital and phenytoin prevented the decrease of GABA but did not reverse the inhibition of GAD.4.The results suggest a role played by the transmitter pool of GABA in the convulsant action of chemoconvulsants and in the anticonvulsant effect of antiepileptics clinically used in petit mal epilepsy.”

“The level of GABA was increased by the treatment with diphenylhydantoin.”

“However, as most of the high levels of Glu and GABA in the brain are intracellular, Glu, … concentrations in the microenvironment of the uptake sites may be sufficiently small so that the ability of phenytoin to inhibit … and GABA transport may contribute significantly to … anticonvulsant property of this drug.”

“ Phenytoin was observed to inhibit competitively the sodium dependent high affinity synaptosomal transport of both glutamate (Glu) and γ-aminobutyric acid (GABA) withKi values of 66±10 and 185±65 μM, respectively.”

“This constrasted with a previous report that the uptakes of Glu and GABA were enhanced by phenytoin.”