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

Epilepsia. 2005 Oct;46(10):1613-9. doi: 10.1111/j.1528-1167.2005.00265.x.


Purpose: 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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / blood
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • Adult
  • Aged
  • Anticonvulsants / blood
  • Anticonvulsants / metabolism
  • Anticonvulsants / therapeutic use*
  • Blood-Brain Barrier / metabolism*
  • Brain / metabolism*
  • Carbamazepine / analogs & derivatives*
  • Carbamazepine / blood
  • Carbamazepine / metabolism
  • Carbamazepine / therapeutic use
  • Child
  • Drug Resistance
  • Drug Resistance, Multiple
  • Epilepsy / blood
  • Epilepsy / drug therapy*
  • Epilepsy / metabolism
  • Female
  • Humans
  • In Vitro Techniques
  • Male
  • Oxcarbazepine
  • Pilot Projects
  • RNA, Messenger / metabolism


  • 10,11-dihydro-10-hydroxycarbamazepine
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Anticonvulsants
  • RNA, Messenger
  • Carbamazepine
  • Oxcarbazepine