Prediction of antiepileptic drug efficacy: The use of intracerebral microdialysis to monitor biophase concentrations

Expert Opinion on Drug Metabolism and Toxicology

Volumn 5, Issue 10, 2009, Pages 1267-1277

  Clinckers, Ralph ^a,b   Smolders, Ilse ^a   Vermoesen, Katia ^a   Michotte, Yvette ^a   Danhof, Meindert ^b   Voskuyl, Rob ^b   Della Pasqua, Oscar ^b  

^a PHARMACEUTICAL INSTITUTE   (Belgium)

^b LEIDEN UNIVERSITY   (Netherlands)

Author keywords

Antiepileptic drugs; Biophase; Blood brain barrier; Epilepsy; Microdialysis; Pharmacodynamic; Pharmacokinetic

Indexed keywords

10,11 DIHYDROXY 10 HYDROXYCARBAMAZEPINE; 3 MERCAPTOPROPIONIC ACID; ANTICONVULSIVE AGENT; CARBAMAZEPINE; CLOMIPRAMINE; DRUG METABOLITE; ETIRACETAM; FELBAMATE; GABAPENTIN; GASTRODIN; GLYCOPROTEIN P; LAMOTRIGINE; MULTIDRUG RESISTANCE PROTEIN; N METHYL DEXTRO ASPARTIC ACID RECEPTOR BLOCKING AGENT; NORFLOXACIN; OXCARBAZEPINE; PHENOBARBITAL; PHENYTOIN; PREGABALIN; PRIMIDONE; UNCLASSIFIED DRUG; VALPROIC ACID; VIGABATRIN;

ACUTE DRUG ADMINISTRATION; ANTICONVULSANT ACTIVITY; BLOOD BRAIN BARRIER; CEREBROSPINAL FLUID; CLINICAL ASSESSMENT TOOL; DRUG BLOOD LEVEL; DRUG DETERMINATION; DRUG DISTRIBUTION; DRUG EFFICACY; DRUG METABOLISM; DRUG MONITORING; DRUG TRANSPORT; EPILEPSY; GENE OVEREXPRESSION; HUMAN; INTRACEREBRAL MICRODIALYSIS; MICRODIALYSIS; NONHUMAN; PHARMACODYNAMICS; PREDICTION; REVIEW; SEIZURE; SUBCUTANEOUS MICRODIALYSIS; TREATMENT RESPONSE;

ANIMALS; ANTICONVULSANTS; BIOLOGICAL TRANSPORT; BLOOD-BRAIN BARRIER; BRAIN; EPILEPSY; HUMANS; MICRODIALYSIS; MODELS, BIOLOGICAL; TIME FACTORS; TISSUE DISTRIBUTION;

EID: 70349391356     PISSN: 17425255     EISSN: None     Source Type: Journal    
DOI: 10.1517/17425250903146903     Document Type: Review

References (98)

1. Engel J, Pedley TA. Epilepsy: a comprehensive textbook: LWW, 2008
2. Kwan P, Brodie MJ. Effectiveness of first antiepileptic drug. Epilepsia 2001;42(10):1255-1260
3. Dreier J, Jurkat-Rott K, Petzold G, et al. Opening of the blood-brain barrier preceding cortical edema in a severe attack of FHM type II. Neurology 2005;64(12):2145-2147 (Pubitemid 40881013)
4. Korn A, Golan H, Melamed I, et al. Focal cortical dysfunction and blood-brain barrier disruption in patients with Postconcussion syndrome. J Clin Neurophysiol 2005;22(1):1-9 (Pubitemid 40194694)
5. Minagar A, Alexander J. Blood-brain barrier disruption in multiple sclerosis. Mult Scler 2003;9(6):540-549 (Pubitemid 37479401)
6. Seiffert E, Dreier J, Ivens S, etal. Lasting blood-brain barrier disruption induces epileptic focus in the rat somatosensory cortex. J Neurosci 2004;24(36):7829-7836 (Pubitemid 39215686)
7. Nitsch C, Klatzo I. Regional patterns of blood-brain barrier breakdown during epileptiform seizures induced by various convulsive agents. J Neurol Sci 1983;59(3):305-322
8. Mihály A, Bozóky B. Immunohistochemical localization of extravasated serum albumin in the hippocampus of human subjects with partial and generalized epilepsies and epileptiform convulsions. Acta Neuropathol 1984;65(1):25-34 (Pubitemid 15191144)
9. Suzuki R, Nitsch C, Fujiwara K, Klatzo I. Regional changes in cerebral blood flow and blood-brain barrier permeability during epileptiform seizures and in acute hypertension in rabbits. J Cereb Blood Flow Metab 1984;4(1):96-102 (Pubitemid 14169324)
10. Cornford E, Oldendorf W. Epilepsy and the blood-brain barrier. Adv Neurol 1986;44:787-812
11. Padou V, Boyet S, Nehlig A. Changes in transport of [14C] alpha-aminoisobutyric acid across the blood-brain barrier during pentylenetetrazol-induced status epilepticus in the immature rat. Epilepsy Res 1995;22(3):175-183 (Pubitemid 3014904)
12. Ilbay G, Sahin D, Ates N. Changes in blood-brain barrier permeability during hot water-induced seizures in rats. Neurol Sci 2003;24(4):232-235 (Pubitemid 37493177)
13. Leroy C, Roch C, Koning E, etal. In the lithium-pilocarpine model of epilepsy, brain lesions are not linked to changes in blood-brain barrier permeability: an autoradiographic study in adult and developing rats. Exp Neurol 2003;182(2):361-372
14. van Vliet E, da Costa Araújo S, Redeker S, et al. Blood-brain barrier leakage may lead to progression of temporal lobe epilepsy. Brain 2007;130(Pt 2):521-534 (Pubitemid 46181105)
15. van Vliet E, Redeker S, Aronica E, et al. Expression of multidrug transporters MRP1, MRP2, and BCRP shortly after status epilepticus, during the latent period, and in chronic epileptic rats. Epilepsia 2005;46(10):1569-1580 • Study demonstrating that overexpression of multidrug transporters during chronic epilepsy importantly affects antiepileptic drug concentrations in the brain. (Pubitemid 44921930)
16. Petito CK, Schaefer JA, Plum F. Ultrastructural characteristics of the brain and blood-brain barrier in experimental seizures. Brain Res 1977;127(2):251-267 (Pubitemid 8107788)
17. Janigro D. Blood-brain barrier, ion homeostatis and epilepsy: possible implications towards the understanding of ketogenic diet mechanisms. Epilepsy Res 1999;37(3):223-232 (Pubitemid 29476520)
18. Thiebaut F, Tsuruo T, Hamada H, et al. Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. Proc Natl Acad Sci USA 1987;84(21):7735-7738
19. Thiebaut F, Tsuruo T, Hamada H, et al. Immunohistochemical localization in normal tissues of different epitopes in the multidrug transport protein P170: evidence for localization in brain capillaries and crossreactivity of one antibody with a muscle protein. J Histochem Cytochem 1989;37(2):159-164 (Pubitemid 19039163)
20. Cordon-Cardo C, O'Brien J, Casals D, et al. Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites. Proc Natl Acad Sci USA 1989;86(2):695-698 (Pubitemid 19037807)
21. Cordon-Cardo C, O'Brien J, Boccia J, et al. Expression of the multidrug resistance gene product (P-glycoprotein) in human normal and tumor tissues. J Histochem Cytochem 1990;38(9):1277-1287 (Pubitemid 20266126)
22. de Boer A, van der Sandt I, Gaillard P. The role of drug transporters at the blood-brain barrier. Annu Rev Pharmacol Toxicol 2003;43:629-656 (Pubitemid 37372656)
23. Balayssac D, Authier N, Cayre A, Coudore F. Does inhibition of P-glycoprotein lead to drug-drug interactions? Toxicol Lett 2005;156(3):319-329
24. Löscher W, Potschka H. Drug resistance in brain diseases and the role of drug efflux transporters. Nat Rev Neurosci 2005;6(8):591-602 • Comprehensive review paper discussing the potential contribution of multidrug transporters in pharmacoresistant epilepsy. (Pubitemid 41059334)
25. Kwan P, Brodie M. Potential role of drug transporters in the pathogenesis of medically intractable epilepsy. Epilepsia 2005;46(2):224-235 (Pubitemid 40194666)
26. Kwan P, Sills G, Butler E, etal. Differential expression of multidrug resistance genes in naïve rat brain. Neurosci Lett 2003;339(1):33-36
27. Chaurasia CS. Invivo microdialysis sampling: theory and applications. Biomed Chromatogr 1999;13(5):317-332 (Pubitemid 29381285)
28. Höcht C, Lazarowski A, Gonzalez NN, et al. Nimodipine restores the altered hippocampal phenytoin pharmacokinetics in a refractory epileptic model. Neurosci Lett 2007;413(2):168-172 (Pubitemid 46177404)
29. Lin LC, Chen YF, Lee WC, et al. Pharmacokinetics of gastrodin and its metabolite p-hydroxybenzyl alcohol in rat blood, brain and bile by microdialysis coupled to LC-MS/MS. J Pharm Biomed Anal 2008;48(3):909-917
30. Graumlich JF, McLaughlin RG, Birkhahn D, etal. Carbamazepine pharmacokinetics-pharmacodynamics in genetically epilepsy-prone rats. Eur J Pharmacol 1999;369(3):305-311 (Pubitemid 29155295)
31. Van Belle K, Sarre S, Ebinger G, et al. Brain, liver and blood distribution kinetics of carbamazepine and its metabolic interaction with clomipramine in rats: a quantitative microdialysis study. J Pharmacol Exp Ther 1995;272(3):1217-22 • Quantitative microdialysis study using the internal standard technique as in vivo calibration method.
32. Patsalos PN, O'Connell MT, Doheny HC, et al. Antiepileptic drug pharmacokinetics in patients with epilepsy using a new microdialysis probe: preliminary observations. Acta Neurochir Suppl 1996;67:59-62
33. Hack A, Busch V, Pascher B, et al. Monitoring of ketogenic diet for carnitine metabolites by subcutaneous microdialysis. Pediatr Res 2006;60(1):93-96 (Pubitemid 44297620)
34. Lindberger M, Tomson T, Stahle L. Validation of microdialysis sampling for subcutaneous extracellular valproic acid in humans. Ther Drug Monit 1998;20(3):358-362 (Pubitemid 28248860)
35. Stähle L, Alm C, Ekquist B, et al. Monitoring free extracellular valproic acid by microdialysis in epileptic patients. Ther Drug Monit 1996;18(1):14-18 (Pubitemid 26033353)
36. Lindberger M, Tomson T, Lars S. Microdialysis sampling of carbamazepine, phenytoin and phenobarbital in subcutaneous extracellular fluid and subdural cerebrospinal fluid in humans: an invitro and invivo study of adsorption to the sampling device. Pharmacol Toxicol 2002;91(4):158-165 (Pubitemid 35216917)
37. Lindberger M, Tomson T, Ohman I, et al. Estimation of topiramate in subdural cerebrospinal fluid, subcutaneous extracellular fluid, and plasma: a single case microdialysis study. Epilepsia 1999;40(6):800-802 (Pubitemid 29260724)
38. Lindberger M, Tomson T, Wallstedt L, Stahle L. Distribution of valproate to subdural cerebrospinal fluid, subcutaneous extracellular fluid, and plasma in humans: a microdialysis study. Epilepsia 2001;42(2):256-261 • Paper demonstrating the feasibility and reliability of using microdialysis in patients. (Pubitemid 32204809)
39. de Lange EC, Ravenstijn PG, Groenendaal D, van Steeg TJ. Toward the prediction of CNS drug-effect profiles in physiological and pathological conditions using microdialysis and mechanism-based pharmacokinetic- pharmacodynamic modeling. AAPS J 2005;7(3):E532-43 •• Review on the potential of microdialysis for drug effect prediction. (Pubitemid 41631735)
40. Derendorf H, Hochhaus G, Mollmann H, etal. Receptor-based pharmacokinetic-pharmacodynamic analysis of corticosteroids. J Clin Pharmacol 1993;33(2):115-123 (Pubitemid 23089632)
41. Hammarlund-Udenaes M, Paalzow LK, de Lange EC. Drug equilibration across the blood-brain barrier - pharmacokinetic considerations based on the microdialysis method. Pharm Res 1997;14(2):128-134 • Paper describing the processes driving unbound brain concentrations in relation to the blood concentration profile. (Pubitemid 27146353)
42. de Lange EC, Danhof M. Considerations in the use of cerebrospinal fluid pharmacokinetics to predict brain target concentrations in the clinical setting: implications of the barriers between blood and brain. Clin Pharmacokinet 2002;41(10):691-703 (Pubitemid 34948192)
43. Collins JM, Dedrick RL. Distributed model for drug delivery to CSF and brain tissue. Am J Physiol 1983;245(3):R303-10
44. Wang Y, Welty DF. The simultaneous estimation of the influx and efflux blood-brain barrier permeabilities of gabapentin using a microdialysis- pharmacokinetic approach. Pharm Res 1996;13(3):398-403 (Pubitemid 126422236)
45. Sechi GP, Petruzzi V, Rosati G, et al. Brain interstitial fluid and intracellular distribution of phenytoin. Epilepsia 1989;30(2):235-239 (Pubitemid 19095116)
46. Wilder BJ, Ramsay RE, Willmore LJ, et al. Efficacy of intravenous phenytoin in the treatment of status epilepticus: kinetics of central nervous system penetration. Ann Neurol 1977;1(6):511-518
47. Gross PM, Sposito NM, Pettersen SE, Fenstermacher JD. Differences in function and structure of the capillary endothelium in gray matter, white matter and a circumventricular organ of rat brain. Blood Vessels 1986;23(6):261-270
48. de Lange EC, Danhof M, de Boer AG, Breimer DD. Methodological considerations of intracerebral microdialysis in pharmacokinetic studies on drug transport across the blood-brain barrier. Brain Res Brain Res Rev 1997;25(1):27-49 •• Paper highlighting the methodological issues in microdialysis sampling for pharmacokinetic studies. (Pubitemid 27459719)
49. Ungerstedt U, Pycock C. Functional correlates of dopamine neurotransmission. Bull Schweiz Akad Med Wiss 1974;30(1-3):44-55
50. Rada P, Tucci S, Perez J, etal. Invivo monitoring of gabapentin in rats: a microdialysis study coupled to capillary electrophoresis and laser-induced fluorescence detection. Electrophoresis 1998;19(16-17):2976-2980
51. Welty DF, Schielke GP, Vartanian MG, Taylor CP. Gabapentin anticonvulsant action in rats: disequilibrium with peak drug concentrations in plasma and brain microdialysate. Epilepsy Res 1993;16(3):175-181
52. Luer MS, Hamani C, Dujovny M, et al. Saturable transport of gabapentin at the blood-brain barrier. Neurol Res 1999;21(6):559-562 (Pubitemid 29426887)
53. Thomas SA, Segal MB. The transport of the anti-HIV drug, 2′,3′-didehydro-3′-deoxythymidine (D4T), across the blood-brain and blood-cerebrospinal fluid barriers. Br J Pharmacol 1998;125(1):49-54
54. Walker MC, Tong X, Perry H, et al. Comparison of serum, cerebrospinal fluid and brain extracellular fluid pharmacokinetics of lamotrigine. Br J Pharmacol 2000;130(2):242-248 •• Study investigating drug disposition in different body compartments simultaneously. (Pubitemid 30261033)
55. Cornford EM, Young D, Paxton JW, Sofia RD. Blood-brain barrier penetration of felbamate. Epilepsia 1992;33(5):944-954
56. Pardridge WM, Sakiyama R, Fierer G. Transport of propranolol and lidocaine through the rat blood-brain barrier. Primary role of globulin-bound drug. J Clin Invest 1983;71(4):900-908 (Pubitemid 13163262)
57. Urien S, Pinquier JL, Paquette B, et al. Effect of the binding of isradipine and darodipine to different plasma proteins on their transfer through the rat blood-brain barrier. Drug binding to lipoproteins does not limit the transfer of drug. J Pharmacol Exp Ther 1987;242(1):349-353 (Pubitemid 17112302)
58. Walker MC, Alavijeh MS, Shorvon SD, Patsalos PN. Microdialysis study of the neuropharmacokinetics of phenytoin in rat hippocampus and frontal cortex. Epilepsia 1996;37(5):421-427 (Pubitemid 26140595)
59. Tong X, Ratnaraj N, Patsalos PN. Vigabatrin extracellular pharmacokinetics and concurrent gamma-aminobutyric acid neurotransmitter effects in rat frontal cortex and hippocampus using microdialysis. Epilepsia 2009;50(2):174-183
60. Wang X, Ratnaraj N, Patsalos PN. The pharmacokinetic inter-relationship of tiagabine in blood, cerebrospinal fluid and brain extracellular fluid (frontal cortex and hippocampus). Seizure 2004;13(8):574-581 (Pubitemid 39549830)
61. Abbott NJ, Revest PA. Control of brain endothelial permeability. Cerebrovasc Brain Metab Rev 1991;3(1):39-72
62. de Lange EC, Hesselink MB, Danhof M, et al. The use of intracerebral microdialysis to determine changes in blood-brain barrier transport characteristics. Pharm Res 1995;12(1):129-133
63. Bolwig TG, Hertz MM, Holm-Jensen J. Blood-brain barrier during electroshock seizures in the rat. Eur J Clin Invest 1977;7(2):95-100 (Pubitemid 8288184)
64. Seifert G, Huttmann K, Schramm J, Steinhauser C. Enhanced relative expression of glutamate receptor 1 flip AMPA receptor subunits in hippocampal astrocytes of epilepsy patients with Ammon's horn sclerosis. J Neurosci 2004;24(8):1996-2003 (Pubitemid 38292813)
65. Oby E, Janigro D. The blood-brain barrier and epilepsy. Epilepsia 2006;47(11):1761-1774
66. van Vliet E, van Schaik R, Edelbroek P, et al. Region-specific overexpression of P-glycoprotein at the blood-brain barrier affects brain uptake of phenytoin in epileptic rats. J Pharmacol Exp Ther 2007;322(1):141-7 •• Quantitative microdialysis study demonstrating the impact of epilepsy-induced efflux transporter overexpression on brain disposition of AEDs. (Pubitemid 46956371)
67. Sisodiya SM. Mechanisms of antiepileptic drug resistance. Curr Opin Neurol 2003;16(2):197-201
68. Potschka H, Löscher W. Invivo evidence for P-glycoprotein-mediated transport of phenytoin at the blood-brain barrier of rats. Epilepsia 2001;42(10):1231-1240 (Pubitemid 33070662)
69. Potschka H, Löscher W. Multidrug resistance-associated protein is involved in the regulation of extracellular levels of phenytoin in the brain. Neuroreport 2001;12(11):2387-2389 (Pubitemid 32684582)
70. Potschka H, Fedrowitz M, Löscher W. P-glycoprotein and multidrug resistance-associated protein are involved in the regulation of extracellular levels of the major antiepileptic drug carbamazepine in the brain. Neuroreport 2001;12(16):3557-3560 (Pubitemid 33065498)
71. Potschka H, Fedrowitz M, Löscher W. P-Glycoprotein-mediated efflux of phenobarbital, lamotrigine, and felbamate at the blood-brain barrier: evidence from microdialysis experiments in rats. Neurosci Lett 2002;327(3):173-176 (Pubitemid 34756625)
72. Clinckers R, Smolders I, Meurs A, etal. Quantitative invivo microdialysis study on the influence of multidrug transporters on the blood-brain barrier passage of oxcarbazepine: concomitant use of hippocampal monoamines as pharmacodynamic markers for the anticonvulsant activity. J Pharmacol Exp Ther 2005;314(2):725-731 •• Study showing the usefulness of measuring target site pharmacokinetics and pharmacodynamics in the optimization of pharmacotherapy in epilepsy. (Pubitemid 41043855)
73. Potschka H, Fedrowitz M, Loscher W. Brain access and anticonvulsant efficacy of carbamazepine, lamotrigine, and felbamate in ABCC2/MRP2-deficient TR- rats. Epilepsia 2003;44(12):1479-1486 (Pubitemid 38020180)
74. Baltes S, Fedrowitz M, Tortos CL, et al. Valproic acid is not a substrate for P-glycoprotein or multidrug resistance proteins 1 and 2 in a number of invitro and invivo transport assays. J Pharmacol Exp Ther 2007;320(1):331-343 (Pubitemid 46025748)
75. Potschka H, Baltes S, Loscher W. Inhibition of multidrug transporters by verapamil or probenecid does not alter blood-brain barrier penetration of levetiracetam in rats. Epilepsy Res 2004;58(2-3):85-91 (Pubitemid 38553945)
76. Scism JL, Powers KM, Artru AA, et al. Probenecid-inhibitable efflux transport of valproic acid in the brain parenchymal cells of rabbits: a microdialysis study. Brain Res 2000;884(1-2):77-86
77. Hesselink MB, Smolders H, Eilbacher B, et al. The role of probenecid-sensitive organic acid transport in the pharmacokinetics of N-methyl-D-aspartate receptor antagonists acting at the glycine(B)-site: microdialysis and maximum electroshock seizures studies. J Pharmacol Exp Ther 1999;290(2):543-550 (Pubitemid 29355110)
78. Clinckers R, Smolders I, Michotte Y, et al. Impact of efflux transporters and of seizures on the pharmacokinetics of oxcarbazepine metabolite in the rat brain. Br J Pharmacol 2008;155(7):1127-1138 •• The first paper to simultaneously model the pharmacokinetics in plasma and brain.
79. Loscher W, Dekundy A, Nagel J, et al. mGlu1 and mGlu5 receptor antagonists lack anticonvulsant efficacy in rodent models of difficult-to-treat partial epilepsy. Neuropharmacology 2006;50(8):1006-1015 (Pubitemid 43794906)
80. Rizzi M, Caccia S, Guiso G, etal. Limbic seizures induce P-glycoprotein in rodent brain: functional implications for pharmacoresistance. J Neurosci 2002;22(14):5833-5839
81. Potschka H, Loscher W. A comparison of extracellular levels of phenytoin in amygdale and hippocampus of kindled and non-kindled rats. Neuroreport 2002;13(1):167-171 (Pubitemid 34102049)
82. Scheyer RD, During MJ, Hochholzer JM, et al. Phenytoin concentrations in the human brain: an invivo microdialysis study. Epilepsy Res 1994;18(3):227-232
83. Tisdall M, Russo S, Sen J, etal. Free phenytoin concentration measurement in brain extracellular fluid: a pilot study. Br J Neurosurg 2006;20(5):285-289 (Pubitemid 44863787)
84. Rambeck B, Jurgens UH, May TW, et al. Comparison of brain extracellular fluid, brain tissue, cerebrospinal fluid, and serum concentrations of antiepileptic drugs measured intraoperatively in patients with intractable epilepsy. Epilepsia 2006;47(4):681-94 •• Study in which intra-operative microdialysis was performed in epilepsy patients investigating body disposition of AEDs.
85. Graff CL, Pollack GM. Nasal drug administration: potential for targeted central nervous system delivery. J Pharm Sci 2005;94(6):1187-1195 (Pubitemid 40904183)
86. Pardridge WM. The blood-brain barrier: bottleneck in brain drug development. NeuroRx 2005;2(1):3-14 (Pubitemid 40128022)
87. Pardridge WM. The blood-brain barrier and neurotherapeutics. NeuroRx 2005;2(1):1-2
88. Battaglia G, La Russa M, Bruno V, et al. Systemically administered D-glucose conjugates of 7-chlorokynurenic acid are centrally available and exert anticonvulsant activity in rodents. Brain Res 2000;860(1-2):149-156 (Pubitemid 30155848)
89. Fisher RS, Ho J. Potential new methods for antiepileptic drug delivery. CNS Drugs 2002;16(9):579-593 (Pubitemid 34941126)
90. Wolfe TR, Macfarlane TC. Intranasal midazolam therapy for pediatric status epilepticus. Am J Emerg Med 2006;24(3):343-346
91. Czapp M, Bankstahl JP, Zibell G, Potschka H. Brain penetration and anticonvulsant efficacy of intranasal phenobarbital in rats. Epilepsia 2008;49(7):1142-1150 (Pubitemid 351991394)
92. Ahmad S, Fowler LJ, Whitton PS. Effects of acute and chronic lamotrigine treatment on basal and stimulated extracellular amino acids in the hippocampus of freely moving rats. Brain Res 2004;1029(1):41-47 (Pubitemid 39463305)
93. Ahmad S, Fowler LJ, Whitton PS. Effect of acute and chronic lamotrigine on basal and stimulated extracellular 5-hydroxytryptamine and dopamine in the hippocampus of the freely moving rat. Br J Pharmacol 2004;142(1):136-142 (Pubitemid 38698202)
94. Clinckers R, Smolders I, Meurs A, et al. Hippocampal dopamine and serotonin elevations as pharmacodynamic markers for the anticonvulsant efficacy of oxcarbazepine and 10,11-dihydro-10-hydroxycarbamazepine. Neurosci Lett 2005;390(1):48-53 (Pubitemid 41317788)
95. Chenel M, Limosin A, Marchand S, et al. Norfloxacin-induced electroencephalogram alteration and seizures in rats are not triggered by enhanced levels of intracerebral glutamate. Antimicrob Agents Chemother 2003;47(11):3660-3662 (Pubitemid 37345744)
96. Smolders I, Gousseau C, Marchand S, et al. Convulsant and subconvulsant doses of norfloxacin in the presence and absence of biphenylacetic acid alter extracellular hippocampal glutamate but not gamma-aminobutyric acid levels in conscious rats. Antimicrob Agents Chemother 2002;46(2):471-477 (Pubitemid 34087198)
97. Crick EW, Osorio I, Bhavaraju NC, et al. An investigation into the pharmacokinetics of 3-mercaptopropionic acid and development of a steady-state chemical seizure model using invivo microdialysis and electrophysiological monitoring. Epilepsy Res 2007;74(2-3):116-125 (Pubitemid 46654740)
98. Feng MR, Turluck D, Burleigh J, et al. Brain microdialysis and PK/PD correlation of pregabalin in rats. Eur J Drug Metab Pharmacokinet 2001;26(1-2):123-128 (Pubitemid 32802404)