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

Nicola Marchi, Giovanna Guiso, Massimo Rizzi, Susanne Pirker, Klaus Novak, Thomas Czech, Christoph Baumgartner, Damir Janigro, Silvio Caccia, Annamaria Vezzani

Research output: Contribution to journalArticle

Abstract

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 (Css) 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 Css. 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.

Original languageEnglish
Pages (from-to)1613-1620
Number of pages8
JournalEpilepsia
Volume46
Issue number10
DOIs
Publication statusPublished - Oct 2005

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Azepines
Epilepsy
Brain
Pharmaceutical Preparations
Messenger RNA
oxcarbazepine
P-Glycoprotein
Blood-Brain Barrier
Reverse Transcriptase Polymerase Chain Reaction
Seizures
High Pressure Liquid Chromatography
Cell Line

Keywords

  • Antiepileptic drugs
  • Blood-brain barrier
  • P-glycoprotein
  • Pharmacoresistance

ASJC Scopus subject areas

  • Clinical Neurology
  • Neuroscience(all)

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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. / Marchi, Nicola; Guiso, Giovanna; Rizzi, Massimo; Pirker, Susanne; Novak, Klaus; Czech, Thomas; Baumgartner, Christoph; Janigro, Damir; Caccia, Silvio; Vezzani, Annamaria.

In: Epilepsia, Vol. 46, No. 10, 10.2005, p. 1613-1620.

Research output: Contribution to journalArticle

Marchi, Nicola ; Guiso, Giovanna ; Rizzi, Massimo ; Pirker, Susanne ; Novak, Klaus ; Czech, Thomas ; Baumgartner, Christoph ; Janigro, Damir ; Caccia, Silvio ; Vezzani, Annamaria. / 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. In: Epilepsia. 2005 ; Vol. 46, No. 10. pp. 1613-1620.
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abstract = "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 (Css) 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 Css. 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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T1 - 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

AU - Marchi, Nicola

AU - Guiso, Giovanna

AU - Rizzi, Massimo

AU - Pirker, Susanne

AU - Novak, Klaus

AU - Czech, Thomas

AU - Baumgartner, Christoph

AU - Janigro, Damir

AU - Caccia, Silvio

AU - Vezzani, Annamaria

PY - 2005/10

Y1 - 2005/10

N2 - 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 (Css) 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 Css. 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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KW - Antiepileptic drugs

KW - Blood-brain barrier

KW - P-glycoprotein

KW - Pharmacoresistance

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