Volume-Selective Proton MR Spectroscopy for In Vitro Quantification of Anticonvulsants

The administration of anticonvulsant drugs is clinically monitored by checking seizure frequency and by determining the serum concentration of the drug. In a few reports, drug concentrations in brain parenchyma have been determined using ex vivo techniques. Little is known about the in vivo concentration in the brain parenchyma.
The goals of this project were to characterize the NMR spectra of the anticonvulsants at therapeutic concentrations, to determine the minimum detectable concentrations, and to quantify the drugs non-invasively.
Volume-selective 1H-MRS was performed under standard clinical conditions using a single-voxel STEAM (Stimulated Echo Acquisition Mode) sequence at 1.5 T. Spectra of the anticonvulsants carbamazepine, phenobarbital, phenytoin, and valproate were acquired in vitro in hydrous solutions under increasing dilution.
Phenytoin, phenobarbital, and valproate were detectable below maximum therapeutic serum concentrations. Within therapeutic ranges, there was good agreement in concentrations determined by 1H-MRS and those by standard fluorescence polarization immunoassay. Due to the absence of signals of brain metabolites, the aromatic protons of phenobarbital, phenytoin, and carbamazepine with resonance lines around 7.4 ppm allow the drugs to be detected. Valproate with two resonances around 1.2 ppm should be differentiable from potential brain metabolites by using a non-linear analysis of the brain spectrum. Volume-selective 1H-MRS is therefore expected to be able to monitor anticonvulsant therapy in vivo.