title: In vitro responsiveness of human-drug-resistant tissue to antiepileptic drugs: insights into the mechanisms of pharmacoresistance.
abstract: Pharmacoresistance in epileptic patients may be ascribed to at least two, not mutually exclusive, mechanisms: a pharmacokinetic mechanism and a decreased sensitivity or availability of targets to antiepileptic drugs (AEDs; i.e., carbamazepine and phenytoin (CBZ, PHT)). Brain:plasma drug concentration ratios were determined intraoperatively during lobectomies performed to alleviate drug-resistant seizures. The brain:plasma ratio of CBZ was 1.48 when therapeutic serum levels (15-34 microM) were achieved. When concentrations of CBZ found in multiple-drug-resistant brain were directly applied to human cortical slices from drug-resistant patients made hyperexcitable and hypersynchronous by Mg(2+)-free media, bursting frequency was not significantly affected and overall excitability was reduced by 40%. Similar results were obtained for PHT. At higher AED concentrations (60-200 microM), a dose-dependent decrease of bursting frequency and amplitude was observed. Slices from drug-resistant epileptic patients made hypersynchronous/hyperexcitable by elevated potassium or inhibition of GABA-A receptors behaved similarly. Of note is the response of slices from human multiple-drug-resistant brain, which was greater than in rodent cortex from naive animals. Taken together, our results support the hypothesis that multiple drug resistance to AEDs involves cerebrovascular changes that impede the achievement of appropriate drug levels in the central nervous system.
authors.affiliation: Cerebrovascular Research Center, The Cleveland Clinic, OH 44195, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Oby
authors.forename: Silvio
authors.initials: S
authors.lastname: Caccia
authors.forename: Annamaria
authors.initials: A
authors.lastname: Vezzani
authors.forename: Gabriel
authors.initials: G
authors.lastname: Moeddel
authors.forename: Kerri
authors.initials: K
authors.lastname: Hallene
authors.forename: Giovanna
authors.initials: G
authors.lastname: Guiso
authors.forename: Tamer
authors.initials: T
authors.lastname: Said
authors.forename: William
authors.initials: W
authors.lastname: Bingaman
authors.forename: Nicola
authors.initials: N
authors.lastname: Marchi
authors.forename: Christoph
authors.initials: C
authors.lastname: Baumgartner
authors.forename: Susanne
authors.initials: S
authors.lastname: Pirker
authors.forename: Thomas
authors.initials: T
authors.lastname: Czech
authors.forename: Giorgio
authors.initials: G
authors.lastname: Lo Russo
authors.forename: Damir
authors.initials: D
authors.lastname: Janigro
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage* / Q000097:blood / Q000134:cerebrospinal fluid; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004351:Drug Resistance; D004827:Epilepsy / Q000188:drug therapy / Q000503:physiopathology*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007223:Infant; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D051379:Mice; D008875:Middle Aged; D018408:Patch-Clamp Techniques / Q000379:methods; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats
chemical_list: D000927:Anticonvulsants; D011189:Potassium Chloride