Volume-selective proton MR spectroscopy for in-vitro quantification of anticonvulsants

Administration of anticonvulsant drugs is clinically monitored by checking seizure frequency and by determining the serum concentration of the drug. I n a few reports, drug concentrations in brain parenchyma have been determin ed using ex vivo techniques. Little is known about the in vivo concentratio n in the brain parenchyma. Our goals were to characterise the NMR spectra o f the anticonvulsants at therapeutic concentrations, to determine the minim um detectable concentrations, and to quantify the drugs noninvasively. Volu me-selective 1H-MR spectroscopy (MRS) was performed under standard clinical conditions using a single-voxel STEAM (stimulated-echo acquisition mode) s equence at 1.5 T. Spectra of the anticonvulsants carbamazepine, phenobarbit al, phenytoin and valproate were acquired in vitro in hydrous solutions at increasing dilution. Phenytoin, phenobarbital and valproate were detectable below maximum therapeutic serum concentrations. Within therapeutic ranges, there was good agreement between concentrations determined by 1H-MRS and t hose by standard fluorescence polarisation immunoassay. Due to the absence of signals of brain metabolites, the aromatic protons of phenobarbital, phe nytoin and carbamazepine, with resonance lines around 7.4 ppm, allow the dr ugs to be detected. Valproate, with two resonances around 1.2 ppm, should b e differentiable from potential brain metabolites using nonlinear analysis of the brain spectrum. Volume-selective 1H-MRS is therefore expected to be able to monitor anticonvulsant therapy in vivo.