title: Comparison of brain extracellular fluid, brain tissue, cerebrospinal fluid, and serum concentrations of antiepileptic drugs measured intraoperatively in patients with intractable epilepsy.
abstract: OBJECTIVE
  The mechanisms of drug resistance in epilepsy are only incompletely understood. According to a current concept, overexpression of drug efflux transporters at the blood-brain barrier may reduce levels of antiepileptic drugs (AEDs) in epileptogenic brain tissue. Increased expression of drug efflux transporters such as P-glycoprotein has been found in brain tissue surgically resected from patients with medically intractable epilepsy, but it is not known whether this leads to decreased extracellular (interstitial) AED concentrations in affected brain regions. This prompted us to measure concentrations of AEDs in the extracellular space of human neocortical tissue by using intraoperative microdialysis (IOMD) in those parts of the brain that had to be removed for therapeutic reasons. For comparison, AED levels were determined in brain tissue, subarachnoid CSF, and serum.
  
  
  METHODS
  Concentrations of carbamazepine (CBZ), 10-hydroxy-carbazepine (10-OH-CZ, metabolite of oxcarbazepine), lamotrigine (LTG), levetiracetam (LEV), topiramate, or phenytoin were determined by using one to four catheters during IOMD in the medial temporal gyrus. Furthermore, to calculate the individual recovery of every catheter, an in vitro microdialysis was performed with ultrafiltrate of serum concurrently obtained from the respective patient. In addition, AED levels were determined in the resected brain tissue, CSF, and serum of the same patients. Altogether 22 pharmacoresistant epilepsy patients (nine male, 13 female patients; age 15-54 years) with complex partial seizures or secondarily generalized seizures were involved. In a first series, IOMD samples 40 min after beginning of the microdialysis (flow rate, 1 microl/min), and in a second series, continuous measurements 25, 30, 35, and 40 min from the beginning were evaluated (flow rate, 2 microl/min). With in vitro recovery data of the individual catheters, the concentration in the extracellular space (ECS) was estimated.
  
  
  RESULTS
  AED concentrations in the ECS of the cortex measured by catheters located at a distance of 0.6 cm differed markedly in some patients, whereas concentrations in the ultrafiltrate of the serum of the respective patients measured with the same catheters varied only slightly. Furthermore, ECS concentrations related to the ultrafiltrate of serum showed considerable interindividual variations. The high intra- and interindividual variation of ECS concentrations is demonstrated by the low correlation between concentrations in ECS and the ultrafiltrate of serum (CBZ, r= 0.41; 10-OH-CZ, r= 0.42; LTG, r= 0.27) in contrast to the high correlation between brain tissue concentration and the ultrafiltrate of serum (CBZ, r= 0.97; 10-OH-CZ, r= 0.88; LTG, r= 0.98) in the same group of patients. When comparing AED concentrations in the ECS with those in the CSF, ECS concentrations were significantly lower for CBZ, 10-OH-CZ, LTG, and LEV.
  
  
  CONCLUSIONS
  The data demonstrate that AED concentrations show a considerable intraindividual and interindividual variation in the ECS of cortical regions. Furthermore, the ECS concentration of several AEDs is significantly lower than their CSF concentration in patients with intractable epilepsy. However, in the absence of data from nonepileptic tissues, it is not possible to judge whether the present findings relate to overexpression of multidrug transporters in the brain. Instead, the present study illustrates the methodologic difficulties involved in performing IOMD studies in patients and may thus be helpful for future approaches aimed at elucidating the role of multidrug transporters in epilepsy.
authors.affiliation: Biochemical Laboratory of the Epilepsy Research Foundation, University of Münster, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Rambeck
authors.forename: Uwe H
authors.initials: UH
authors.lastname: Jürgens
authors.forename: Theodor W
authors.initials: TW
authors.lastname: May
authors.forename: Heinz Wolfgang
authors.initials: HW
authors.lastname: Pannek
authors.forename: Friedrich
authors.initials: F
authors.lastname: Behne
authors.forename: Alois
authors.initials: A
authors.lastname: Ebner
authors.forename: Ali
authors.initials: A
authors.lastname: Gorji
authors.forename: Heidrun
authors.initials: H
authors.lastname: Straub
authors.forename: Erwin-Josef
authors.initials: EJ
authors.lastname: Speckmann
authors.forename: Bernd
authors.initials: B
authors.lastname: Pohlmann-Eden
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Löscher
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism*; D001921:Brain / Q000378:metabolism* / Q000601:surgery*; D001923:Brain Chemistry; D002540:Cerebral Cortex / Q000737:chemistry / Q000378:metabolism; D018432:Drug Resistance, Multiple; D004827:Epilepsy / Q000097:blood / Q000378:metabolism* / Q000601:surgery*; D045604:Extracellular Fluid / Q000737:chemistry / Q000378:metabolism; D005260:Female; D006440:Hemofiltration; D006801:Humans; D008297:Male; D017551:Microdialysis; D008875:Middle Aged; D016343:Monitoring, Intraoperative / Q000379:methods; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D013346:Subarachnoid Space / Q000737:chemistry / Q000378:metabolism; D013702:Temporal Lobe / Q000737:chemistry / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000927:Anticonvulsants; D027425:ATP-Binding Cassette, Sub-Family C Proteins