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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
Author(s) -
Marchi Nicola,
Guiso Giovanna,
Rizzi Massimo,
Pirker Susanne,
Novak Klaus,
Czech Thomas,
Baumgartner Christoph,
Janigro Damir,
Caccia Silvio,
Vezzani Annamaria
Publication year - 2005
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/j.1528-1167.2005.00265.x
Subject(s) - oxcarbazepine , azepine , epilepsy , medicine , psychology , carboxamide , neuroscience , pharmacology , chemistry , stereochemistry , carbamazepine
Summary: 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.