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

被引:59
作者
Marchi, N
Guiso, G
Rizzi, M
Pirker, S
Novak, K
Czech, T
Baumgartner, C
Janigro, D
Caccia, S
Vezzani, A
机构
[1] Mario Negri Inst Pharmacol Res, Dept Neurosci, Lab Exp Neurol, I-20157 Milan, Italy
[2] Univ Vienna, Dept Neurol, Vienna, Austria
[3] Univ Vienna, Dept Neurosurg, Vienna, Austria
[4] Cleveland Clin, Cerebrovasc Res Ctr, Cleveland, OH 44106 USA
关键词
antiepileptic drugs; blood-brain barrier; P-glycoprotein; pharmacoresistance;
D O I
10.1111/j.1528-1167.2005.00265.x
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
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.
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页码:1613 / 1619
页数:7
相关论文
共 33 条
[1]   Expression and cellular distribution of multidrug resistance-related proteins in the hippocampus of patients with mesial temporal lobe epilepsy [J].
Aronica, E ;
Gorter, JA ;
Ramkema, M ;
Redeker, S ;
Özbas-Gerçeker, F ;
van Vliet, EA ;
Scheffer, GL ;
Scheper, RJ ;
van der Valk, P ;
Baayen, JC ;
Troost, D .
EPILEPSIA, 2004, 45 (05) :441-451
[2]   Expression and cellular distribution of multidrug transporter proteins in two major causes of medically intractable epilepsy: Focal cortical dysplasia and glioneuronal tumors [J].
Aronica, E ;
Gorter, JA ;
Jansen, GH ;
Van Veelen, CWM ;
Van Rijen, PC ;
Leenstra, S ;
Ramkema, M ;
Scheffer, GL ;
Scheper, RJ ;
Troost, D .
NEUROSCIENCE, 2003, 118 (02) :417-429
[3]   Spotlight on oxcarbazepine in epilepsy [J].
Bang, LM ;
Goa, KL .
CNS DRUGS, 2004, 18 (01) :57-61
[4]   Overexpression of multiple drug resistance genes in endothelial cells from patients with refractory epilepsy [J].
Dombrowski, SM ;
Desai, SY ;
Marroni, M ;
Cucullo, L ;
Goodrich, K ;
Bingaman, W ;
Mayberg, MR ;
Bengez, L ;
Janigro, D .
EPILEPSIA, 2001, 42 (12) :1501-1506
[5]   Tuberous sclerosis associated with MDR1 gene expression and drug-resistant epilepsy [J].
Lazarowski, A ;
Sevlever, G ;
Taratuto, A ;
Massaro, M ;
Rabinowicz, A .
PEDIATRIC NEUROLOGY, 1999, 21 (04) :731-734
[6]   Role of multidrug transporters in pharmacoresistance to antiepileptic drugs [J].
Löscher, W ;
Potschka, H .
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2002, 301 (01) :7-14
[7]  
Ma Qiang, 2002, Di Yi Jun Yi Da Xue Xue Bao, V22, P264
[8]   Significance of MDR1 and multiple drug resistance in refractory human epileptic brain [J].
Marchi, Nicola ;
Hallene, Kerri L. ;
Kight, Kelly M. ;
Cucullo, Luca ;
Moddel, Gabriel ;
Bingaman, William ;
Dini, Gabriele ;
Vezzani, Annamaria ;
Janigro, Damir .
BMC MEDICINE, 2004, 2 (1)
[9]   Vascular and parenchymal mechanisms in multiple drug resistance: a lesson from human epilepsy [J].
Marroni, M ;
Marchi, N ;
Cucullo, L ;
Abbott, NJ ;
Signorelli, K ;
Janigro, D .
CURRENT DRUG TARGETS, 2003, 4 (04) :297-304
[10]   Relationship between expression of multiple drug resistance proteins and p53 tumor suppressor gene proteins in human brain astrocytes [J].
Marroni, M ;
Agrawal, ML ;
Kight, K ;
Hallene, KL ;
Hossain, M ;
Cucullo, L ;
Signorelli, K ;
Namura, S ;
Bingaman, W ;
Janigro, D .
NEUROSCIENCE, 2003, 121 (03) :605-617