Abstract
We performed volume-selective 1H MR spectroscopy (1H-MRS) on 12 patients on valproate monotherapy to detect valproate in vivo in the brain. We also acquired reference valproate spectra in vitro in subphysiological 15 g/l albumin solution in saline, in which valproate showed two resonance peaks at 0.7 and 1.2 ppm and a minimum detection threshold of 240 mg/l. In vivo 1H-MRS spectra in brain showed peaks between 0.6 and 1.6 ppm. Simultaneous serum valproate concentrations did not correlate with these integrated MRS peaks. On follow-up, changes in these signals also did not correlate with increasing serum valproate levels. The inconsistency of in vivo 1H-MRS signals at varying serum levels and the high detection levels in vitro suggest that valproate signals are missed in vivo because valproate is metabolised or strongly bound, presumably to brain macromolecules.
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References
Mattson RM (1995) Efficacy and adverse effects of established and new antiepileptic drugs. Epilepsia 36 [Suppl 2]: 13–26
Schmidt D (1993) Epilepsien und epileptische Anfälle. Thieme, Stuttgart, p. 327
Rambeck B, Schnabel R, May T, Jürgens U, Villagran R (1990) Postmortem serum binding and brain concentrations of antiepileptic drugs in autoptic specimens from 45 epileptic patients. Ther Drug Monit 12: 533–540
Rambeck B, Schnabel R., May T, Jürgens U, Villagran R (1992) Postmortem concentrations of phenytoin in different regions of the brain and in the serum: analysis of autoptic specimens from 24 epileptic patients. Ther Drug Monit 14: 27–35
Rambeck B, Schnabel R, May T, Jürgens U, Villagran R (1993) Postmortem concentrations of phenobarbital, carbamazepine, and its metabolite carbamazepine-10, 11-epoxide in different regions of the brain and in the serum: analysis of autoptic specimens from 51 epileptic patients. Ther Drug Monit 15: 91–98
Shen DD, Ojeman GA, Rapport RL, Dills RL, Friel PN, Levy RH (1992) Low and variable presence of valproic acid in human brain. Neurology 42: 582–585
Braun J, Seyfert S, Bernarding J, Schilling A, Marx P, Tolxdorff T (2001) Volume-selective proton MR spectroscopy for in-vitro quantification of anticonvulsants. Neuroradiology 43: 211–217
Behar KL, Rothman DL, Spencer DD, Petroff OA (1994) Analysis of macromolecule resonances in 1H NMR spectra of human brain. Magn Reson Med 32: 294–302
Pouwels PJ, Frahm J (1998) Regional metabolite concentrations in human brain as determined by quantitative localized proton MRS. Magn Reson Med 39: 53–60
Provencher SW (1993) Estimation of metabolite concentrations from localized in vivo proton NMR spectra. Magn Reson Med 30: 672–679
Auer DP, Gossl C, Schirmer T, Czisch M (2001) Improved analysis of 1H-MR spectra in the presence of mobile lipids. Magn Reson Med 46: 615–618
Hofmann L, Slotboom J, Boesch C, Kreis R (2001) Characterization of the macromolecule baseline in localized (1)H-MR spectra of human brain. Magn Reson Med 46: 855–863
Driessen O, Treuren L, Meijer JWA (1989) Distribution of drugs over whole blood: I. The transport function of whole blood for valproate. Ther Drug Monit 11: 384–389
Driessen O, Treuren L, Meijer JWA, Hermans J (1989) Distribution of drugs over whole blood: II. The transport function of whole blood for phenytoin. Ther Drug Monit 11: 390–400
Eadie MJ, Tyrer JH (1989) Anticonvulsant therapy. Churchill Livingstone, Edinburgh, p. 45
Persson E (1988) Lipoprotein lipase, hepatic lipase and plasma lipolytic activity. Effects of heparin and a low molecular weight heparin fragment (Fragmin). Acta Med Scand 724 [Suppl]: 1–56
Zimmerman CL, Patel IH, Levy RH, Edwards D, Nelson SD, Hutchinson M (1981) Protein binding of valproic acid in the presence of elevated free fatty acids in patient and normal human serum. Epilepsia 22: 11–17
Petroff OA, Rothman DL, Behar KL, Hyder F, Mattson RH (1999) Effects of valproate and other antiepileptic drugs on brain glutamate, glutamine, and GABA in patients with refractory complex partial seizures. Seizure 8: 120–127
Acknowledgements
We are grateful to Dr H. Bohnemeier, H. Dalichow, and S. Wunderlich (Department of Clinical Pharmacology, UKBF, FU Berlin) for their support . We thank Ms. Jean Pietrowicz for carefully proofreading the manuscript.
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Seyfert, S., Bernarding, J. & Braun, J. Volume-selective 1H MR spectroscopy for in vivo detection of valproate in patients with epilepsy. Neuroradiology 45, 295–299 (2003). https://doi.org/10.1007/s00234-003-0973-5
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DOI: https://doi.org/10.1007/s00234-003-0973-5