Effects of gabapentin on brain GABA, homocarnosine, and pyrrolidinone in epilepsy patients.

PURPOSE: Gabapentin (GBP) was introduced as an antiepileptic drug (AED) and has been used in the management of neuropathic pain. We reported that daily dosing increased brain gamma-aminobutyric acid (GABA) in patients with epilepsy. This study was designed to determine how rapidly brain GABA and the GABA metabolites, homocarnosine and pyrrolidinone, increase in response to the first dose of GBP. METHODS: In vivo measurements of GABA, homocarnosine, and pyrrolidinone were made of a 14-cc volume in the occipital cortex by using a 1H spectroscopy with a 2.1-Tesla magnetic resonance spectrometer and an 8-cm surface coil. Six patients (four women) were studied serially after the first oral dose (1,200 mg) of GBP. Five patients (three women) taking a standard daily dose (range, 1,200-2,000 mg) of GBP were rechallenged with a single high dose (2,400 mg). RESULTS: The first dose of GBP increased median brain GABA by 1.3 mM (range, 0.4-1.8 mM) within 1 h. Homocarnosine and pyrrolidinone did not change significantly by 5 h. Daily GBP therapy increased GABA (0.5 mM; 95% CI, 0.2-0.9), homocarnosine (0.3 mM; 95% CI, 0.2-0.4), and pyrrolidinone (0.10 mM; 95% CI, 0.06-0.14). Rechallenging patients taking GBP daily increased median brain GABA by 0.4 mM (range, 0.3-0.5) within 1 h. CONCLUSIONS: GBP promptly elevates brain GABA and presumably offers partial protection against further seizures within hours of the first oral dose. Patients may expect to experience the anticonvulsant effects of increased homocarnosine and pyrrolidinone with daily therapy.

Novel methods for studying new antiepileptic drug pharmacology.

A number of new antiepileptic drugs act by indirect mechanisms and thus produce effects that may not best be measured by traditional blood studies of the drugs and their metabolites. Study of the indirect action of these drugs on GABA-mediated inhibition by microdialysis and nuclear MR spectroscopy has proved more relevant. These new investigative techniques may also prove valuable as compounds affecting glutamate or other excitatory neurotransmitters are developed.

The effect of gabapentin on brain gamma-aminobutyric acid in patients with epilepsy.

Gabapentin has come into clinical use as adjunctive therapy in the treatment of epilepsy. Designed to mimic gamma-aminobutyric acid (GABA), its mechanism of action remains elusive. In vivo measurements of GABA in human brain were made using 1H magnetic resonance spectroscopy. We used a 2.1-T magnetic resonance imager-spectrometer and an 8-cm surface coil to measure a 13.5-cm3 volume in the occipital cortex. GABA levels were measured in 14 patients enrolled in an open-lbel trial of gabapentin. GABA was elevated in patients taking gabapentin compared with 14 complex partial epilepsy patients, matched for antiepileptic drug treatment. Brain GABA levels appeared to be higher in patients taking high-dose gabapentin (3,300-3,600 mg/day) than in those taking standard doses (1,200-2,400 mg/day). Gabapentin appears to increase human brain GABA levels.

Human serum teratogenicity studied by rat embryo culture: epilepsy, anticonvulsant drugs, and nutrition.

Epileptic women have a greater risk for spontaneous abortions and children with birth defects than do nonepileptics. In a unique approach to identifying causes of these problems, we have cultured whole rat embryos for 48 h on blood sera from epileptics. In the first part of the study, three embryos were cultured on each serum sample from 128 different epileptics being treated with either single anticonvulsants or no drug to compare the teratogenicity of these drugs. Sera from subjects receiving either phenobarbital or no drug had comparable frequencies of cultured embryo abnormalities, which were lower than those from subjects taking phenytoin, valproic acid, or carbamazepine. In the second phase of the study, attempts to identify causes for serum teratogenicity led to the finding that the abnormalities and reduced embryo growth produced by many serum samples could be completely overcome by adding vitamins and/or amino acids to the serum. Of 53 samples tested, 32 (60%) were corrected by supplementation (17 of 23 phenytoin, seven of nine phenobarbital, six of 12 carbamazepine, none of six valproic acid, and two of three no drug). Although the results of this study provided a general assessment of drug teratogenicity that agreed with other studies and emphasized the role of nutrition in fetal defects, the importance of individual differences in causes of teratogenicity was also noted.