title: A pilot study on brain-to-plasma partition of 10,11-dyhydro-10-hydroxy-5H-dibenzo(b,f)azepine-5-carboxamide and MDR1 brain expression in epilepsy patients not responding to oxcarbazepine.
abstract: OBJECTIVE
  We measured the brain-to-plasma partition of 10,11-dihydro-10-hydroxy-5H-dibenzo(b,f)azepine-5-carboxamide (10-OHCBZ) in epilepsy patients undergoing surgery to alleviate drug-resistant seizures and administered with different oral doses of oxcarbazepine (OXC). We addressed the possible contribution of the multidrug transporter P-glycoprotein (P-gp or MDR1) in determining 10-OHCBZ brain levels by measuring whether this active metabolite is a substrate of P-gp and the relation between the level of expression of MDR1 and the drug concentration in the same brain tissue specimens.
  
  
  METHODS
  Steady-state plasma and brain concentrations (C(ss)) of 10-OHCBZ were determined intraoperatively in 11 patients by high-performance liquid chromatography (HPLC) with UV detection. The level of expression of MDR1 mRNA was measured in surgically resected brain tissue by reverse transcriptase polymerase chain reaction (RT-PCR). The ability of 10-OHCBZ to act as substate of P-gp was evaluated by measuring its uptake in cell lines expressing different levels of P-gp, in the presence or absence of a selective P-gp inhibitor.
  
  
  RESULTS
  OXC was converted to 10-OHCBZ and to Di-OHCBZ, the two main metabolites measured in plasma. The brain concentrations of the active metabolite 10-OHCBZ did not reflect plasma C(ss). A significant inverse linear correlation was found between 10-OHCBZ brain-to-plasma concentration ratio and the level of brain expression of MDR1 mRNA. In vitro uptake studies demonstrated lower intracellular 10-OHCBZ levels in cells with higher P-gp expression. Intracellular drug concentration was increased by XR9576, a specific P-gp blocker.
  
  
  CONCLUSIONS
  Pharmacologic failure of OXC in pharmacoresistant epilepsy is unlikely to be due to alterations in drug metabolism. 10-OHCBZ does not appear to cross the blood-brain barrier by simple diffusion, and it acts as a substrate of P-gp. The level of expression of MDR1 is inversely correlated with 10-OHCBZ concentration in the epileptic tissue. P-gp may play a role in the pharmacoresistance to OXC by determining the attainment of insufficient concentrations of its active metabolite at neuronal targets.
authors.affiliation: Department of Neuroscience, Mario Negri Institute for Pharmacological Research, Milan, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Marchi
authors.forename: Giovanna
authors.initials: G
authors.lastname: Guiso
authors.forename: Massimo
authors.initials: M
authors.lastname: Rizzi
authors.forename: Susanne
authors.initials: S
authors.lastname: Pirker
authors.forename: Klaus
authors.initials: K
authors.lastname: Novak
authors.forename: Thomas
authors.initials: T
authors.lastname: Czech
authors.forename: Christoph
authors.initials: C
authors.lastname: Baumgartner
authors.forename: Damir
authors.initials: D
authors.lastname: Janigro
authors.forename: Silvio
authors.initials: S
authors.lastname: Caccia
authors.forename: Annamaria
authors.initials: A
authors.lastname: Vezzani
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000097:blood / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000927:Anticonvulsants / Q000097:blood / Q000378:metabolism / Q000627:therapeutic use*; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D002220:Carbamazepine / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000627:therapeutic use; D002648:Child; D004351:Drug Resistance; D018432:Drug Resistance, Multiple; D004827:Epilepsy / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D000078330:Oxcarbazepine; D010865:Pilot Projects; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: C039775:10,11-dihydro-10-hydroxycarbamazepine; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000927:Anticonvulsants; D012333:RNA, Messenger; D002220:Carbamazepine; D000078330:Oxcarbazepine