A pro-convulsive carbamazepine metabolite: Quinolinic acid in drug resistant epileptic human brain
Drugs and their metabolites often produce undesirable effects. These may be due to a number of mechanisms, including biotransformation by P450 enzymes which are not exclusively expressed by hepatocytes but also by endothelial cells in brain from epileptics. The possibility thus exists that the poten...
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| Published in | Neurobiology of disease Vol. 46; no. 3; pp. 692 - 700 |
|---|---|
| Main Authors | , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
Elsevier Inc
01.06.2012
Elsevier |
| Subjects | |
| Online Access | Get full text |
| ISSN | 0969-9961 1095-953X 1095-953X |
| DOI | 10.1016/j.nbd.2012.03.010 |
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| Abstract | Drugs and their metabolites often produce undesirable effects. These may be due to a number of mechanisms, including biotransformation by P450 enzymes which are not exclusively expressed by hepatocytes but also by endothelial cells in brain from epileptics. The possibility thus exists that the potency of systemically administered central nervous system therapeutics can be modulated by a metabolic blood–brain barrier (BBB).
Surgical brain specimens and blood samples (ex vivo) were obtained from drug-resistant epileptic subjects receiving the antiepileptic drug carbamazepine prior to temporal lobectomies. An in vitro blood–brain barrier model was then established using primary cell culture derived from the same brain specimens. The pattern of carbamazepine (CBZ) metabolism was evaluated in vitro and ex vivo using high performance liquid chromatography–mass spectroscopy. Accelerated mass spectroscopy was used to identify 14C metabolites deriving from the parent 14C-carbamazepine.
Under our experimental conditions carbamazepine levels could not be detected in drug resistant epileptic brain ex situ; low levels of carbamazepine were detected in the brain side of the in vitro BBB established with endothelial cells derived from the same patients. Four carbamazepine-derived fractions were detected in brain samples in vitro and ex vivo. HPLC-accelerated mass spectroscopy confirmed that these signals derived from 14C-carbamazepine administered as parental drug. Carbamazepine 10, 11 epoxide (CBZ-EPO) and 10, 11-dihydro-10, 11-dihydrooxy-carbamazepine (DiOH-CBZ) were also detected in the fractions analyzed. 14C-enriched fractions were subsequently analyzed by mass spectrometry to reveal micromolar concentrations of quinolinic acid (QA). Remarkably, the disappearance of carbamazepine-epoxide (at a rate of 5% per hour) was comparable to the rate of quinolinic acid production (3% per hour). This suggested that quinolinic acid may be a result of carbamazepine metabolism. Quinolinic acid was not detected in the brain of patients who received antiepileptic drugs other than carbamazepine prior to surgery or in brain endothelial cultures obtained from a control patient.
Our data suggest that a drug resistant BBB not only impedes drug access to the brain but may also allow the formation of neurotoxic metabolites.
► We studied carbamazepine (CBZ) metabolism in drug-resistant epileptic subjects. ► CBZ metabolites were detected in the brain in vitro and ex vivo. ► Interestingly, a pro-convulsive molecule, quinolinic acid (QA) was also detected. ► QA was absent in brain of patients receiving antiepileptic drugs other than CBZ. ► A drug resistant BBB may allow the formation of neurotoxic metabolites by P450 mechanisms. |
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| AbstractList | Drugs and their metabolites often produce undesirable effects. These may be due to a number of mechanisms, including biotransformation by P450 enzymes which are not exclusively expressed by hepatocytes but also by endothelial cells in brain from epileptics. The possibility thus exists that the potency of systemically administered central nervous system therapeutics can be modulated by a metabolic blood-brain barrier (BBB). Surgical brain specimens and blood samples (ex vivo) were obtained from drug-resistant epileptic subjects receiving the antiepileptic drug carbamazepine prior to temporal lobectomies. An in vitro blood-brain barrier model was then established using primary cell culture derived from the same brain specimens. The pattern of carbamazepine (CBZ) metabolism was evaluated in vitro and ex vivo using high performance liquid chromatography-mass spectroscopy. Accelerated mass spectroscopy was used to identify (14)C metabolites deriving from the parent (14)C-carbamazepine. Under our experimental conditions carbamazepine levels could not be detected in drug resistant epileptic brain ex situ; low levels of carbamazepine were detected in the brain side of the in vitro BBB established with endothelial cells derived from the same patients. Four carbamazepine-derived fractions were detected in brain samples in vitro and ex vivo. HPLC-accelerated mass spectroscopy confirmed that these signals derived from (14)C-carbamazepine administered as parental drug. Carbamazepine 10, 11 epoxide (CBZ-EPO) and 10, 11-dihydro-10, 11-dihydrooxy-carbamazepine (DiOH-CBZ) were also detected in the fractions analyzed. (14)C-enriched fractions were subsequently analyzed by mass spectrometry to reveal micromolar concentrations of quinolinic acid (QA). Remarkably, the disappearance of carbamazepine-epoxide (at a rate of 5% per hour) was comparable to the rate of quinolinic acid production (3% per hour). This suggested that quinolinic acid may be a result of carbamazepine metabolism. Quinolinic acid was not detected in the brain of patients who received antiepileptic drugs other than carbamazepine prior to surgery or in brain endothelial cultures obtained from a control patient. Our data suggest that a drug resistant BBB not only impedes drug access to the brain but may also allow the formation of neurotoxic metabolites.Drugs and their metabolites often produce undesirable effects. These may be due to a number of mechanisms, including biotransformation by P450 enzymes which are not exclusively expressed by hepatocytes but also by endothelial cells in brain from epileptics. The possibility thus exists that the potency of systemically administered central nervous system therapeutics can be modulated by a metabolic blood-brain barrier (BBB). Surgical brain specimens and blood samples (ex vivo) were obtained from drug-resistant epileptic subjects receiving the antiepileptic drug carbamazepine prior to temporal lobectomies. An in vitro blood-brain barrier model was then established using primary cell culture derived from the same brain specimens. The pattern of carbamazepine (CBZ) metabolism was evaluated in vitro and ex vivo using high performance liquid chromatography-mass spectroscopy. Accelerated mass spectroscopy was used to identify (14)C metabolites deriving from the parent (14)C-carbamazepine. Under our experimental conditions carbamazepine levels could not be detected in drug resistant epileptic brain ex situ; low levels of carbamazepine were detected in the brain side of the in vitro BBB established with endothelial cells derived from the same patients. Four carbamazepine-derived fractions were detected in brain samples in vitro and ex vivo. HPLC-accelerated mass spectroscopy confirmed that these signals derived from (14)C-carbamazepine administered as parental drug. Carbamazepine 10, 11 epoxide (CBZ-EPO) and 10, 11-dihydro-10, 11-dihydrooxy-carbamazepine (DiOH-CBZ) were also detected in the fractions analyzed. (14)C-enriched fractions were subsequently analyzed by mass spectrometry to reveal micromolar concentrations of quinolinic acid (QA). Remarkably, the disappearance of carbamazepine-epoxide (at a rate of 5% per hour) was comparable to the rate of quinolinic acid production (3% per hour). This suggested that quinolinic acid may be a result of carbamazepine metabolism. Quinolinic acid was not detected in the brain of patients who received antiepileptic drugs other than carbamazepine prior to surgery or in brain endothelial cultures obtained from a control patient. Our data suggest that a drug resistant BBB not only impedes drug access to the brain but may also allow the formation of neurotoxic metabolites. Drugs and their metabolites often produce undesirable effects. These may be due to a number of mechanisms, including biotransformation by P450 enzymes which are not exclusively expressed by hepatocytes but also by endothelial cells in brain from epileptics. The possibility thus exists that the potency of systemically administered central nervous system therapeutics can be modulated by a metabolic blood–brain barrier (BBB). Surgical brain specimens and blood samples ( ex vivo ) were obtained from drug-resistant epileptic subjects receiving the antiepileptic drug carbamazepine prior to temporal lobectomies. An in vitro blood–brain barrier model was then established using primary cell culture derived from the same brain specimens. The pattern of carbamazepine (CBZ) metabolism was evaluated in vitro and ex vivo using high performance liquid chromatography–mass spectroscopy. Accelerated mass spectroscopy was used to identify 14 C metabolites deriving from the parent 14 C-carbamazepine. Under our experimental conditions carbamazepine levels could not be detected in drug resistant epileptic brain ex situ ; low levels of carbamazepine were detected in the brain side of the in vitro BBB established with endothelial cells derived from the same patients. Four carbamazepine-derived fractions were detected in brain samples in vitro and ex vivo . HPLC-accelerated mass spectroscopy confirmed that these signals derived from 14 C-carbamazepine administered as parental drug. Carbamazepine 10, 11 epoxide (CBZ-EPO) and 10, 11-dihydro-10, 11-dihydrooxy-carbamazepine (DiOH-CBZ) were also detected in the fractions analyzed. 14 C-enriched fractions were subsequently analyzed by mass spectrometry to reveal micromolar concentrations of quinolinic acid (QA). Remarkably, the disappearance of carbamazepine-epoxide (at a rate of 5% per hour) was comparable to the rate of quinolinic acid production (3% per hour). This suggested that quinolinic acid may be a result of carbamazepine metabolism. Quinolinic acid was not detected in the brain of patients who received antiepileptic drugs other than carbamazepine prior to surgery or in brain endothelial cultures obtained from a control patient. Our data suggest that a drug resistant BBB not only impedes drug access to the brain but may also allow the formation of neurotoxic metabolites. Drugs and their metabolites often produce undesirable effects. These may be due to a number of mechanisms, including biotransformation by P450 enzymes which are not exclusively expressed by hepatocytes but also by endothelial cells in brain from epileptics. The possibility thus exists that the potency of systemically administered central nervous system therapeutics can be modulated by a metabolic blood–brain barrier (BBB).Surgical brain specimens and blood samples (ex vivo) were obtained from drug-resistant epileptic subjects receiving the antiepileptic drug carbamazepine prior to temporal lobectomies. An in vitro blood–brain barrier model was then established using primary cell culture derived from the same brain specimens. The pattern of carbamazepine (CBZ) metabolism was evaluated in vitro and ex vivo using high performance liquid chromatography–mass spectroscopy. Accelerated mass spectroscopy was used to identify 14C metabolites deriving from the parent 14C-carbamazepine.Under our experimental conditions carbamazepine levels could not be detected in drug resistant epileptic brain ex situ; low levels of carbamazepine were detected in the brain side of the in vitro BBB established with endothelial cells derived from the same patients. Four carbamazepine-derived fractions were detected in brain samples in vitro and ex vivo. HPLC-accelerated mass spectroscopy confirmed that these signals derived from 14C-carbamazepine administered as parental drug. Carbamazepine 10, 11 epoxide (CBZ-EPO) and 10, 11-dihydro-10, 11-dihydrooxy-carbamazepine (DiOH-CBZ) were also detected in the fractions analyzed. 14C-enriched fractions were subsequently analyzed by mass spectrometry to reveal micromolar concentrations of quinolinic acid (QA). Remarkably, the disappearance of carbamazepine-epoxide (at a rate of 5% per hour) was comparable to the rate of quinolinic acid production (3% per hour). This suggested that quinolinic acid may be a result of carbamazepine metabolism. Quinolinic acid was not detected in the brain of patients who received antiepileptic drugs other than carbamazepine prior to surgery or in brain endothelial cultures obtained from a control patient.Our data suggest that a drug resistant BBB not only impedes drug access to the brain but may also allow the formation of neurotoxic metabolites. Drugs and their metabolites often produce undesirable effects. These may be due to a number of mechanisms, including biotransformation by P450 enzymes which are not exclusively expressed by hepatocytes but also by endothelial cells in brain from epileptics. The possibility thus exists that the potency of systemically administered central nervous system therapeutics can be modulated by a metabolic blood–brain barrier (BBB). Surgical brain specimens and blood samples (ex vivo) were obtained from drug-resistant epileptic subjects receiving the antiepileptic drug carbamazepine prior to temporal lobectomies. An in vitro blood–brain barrier model was then established using primary cell culture derived from the same brain specimens. The pattern of carbamazepine (CBZ) metabolism was evaluated in vitro and ex vivo using high performance liquid chromatography–mass spectroscopy. Accelerated mass spectroscopy was used to identify 14C metabolites deriving from the parent 14C-carbamazepine. Under our experimental conditions carbamazepine levels could not be detected in drug resistant epileptic brain ex situ; low levels of carbamazepine were detected in the brain side of the in vitro BBB established with endothelial cells derived from the same patients. Four carbamazepine-derived fractions were detected in brain samples in vitro and ex vivo. HPLC-accelerated mass spectroscopy confirmed that these signals derived from 14C-carbamazepine administered as parental drug. Carbamazepine 10, 11 epoxide (CBZ-EPO) and 10, 11-dihydro-10, 11-dihydrooxy-carbamazepine (DiOH-CBZ) were also detected in the fractions analyzed. 14C-enriched fractions were subsequently analyzed by mass spectrometry to reveal micromolar concentrations of quinolinic acid (QA). Remarkably, the disappearance of carbamazepine-epoxide (at a rate of 5% per hour) was comparable to the rate of quinolinic acid production (3% per hour). This suggested that quinolinic acid may be a result of carbamazepine metabolism. Quinolinic acid was not detected in the brain of patients who received antiepileptic drugs other than carbamazepine prior to surgery or in brain endothelial cultures obtained from a control patient. Our data suggest that a drug resistant BBB not only impedes drug access to the brain but may also allow the formation of neurotoxic metabolites. ► We studied carbamazepine (CBZ) metabolism in drug-resistant epileptic subjects. ► CBZ metabolites were detected in the brain in vitro and ex vivo. ► Interestingly, a pro-convulsive molecule, quinolinic acid (QA) was also detected. ► QA was absent in brain of patients receiving antiepileptic drugs other than CBZ. ► A drug resistant BBB may allow the formation of neurotoxic metabolites by P450 mechanisms. Abstract Drugs and their metabolites often produce undesirable effects. These may be due to a number of mechanisms, including biotransformation by P450 enzymes which are not exclusively expressed by hepatocytes but also by endothelial cells in brain from epileptics. The possibility thus exists that the potency of systemically administered central nervous system therapeutics can be modulated by a metabolic blood–brain barrier (BBB). Surgical brain specimens and blood samples ( ex vivo ) were obtained from drug-resistant epileptic subjects receiving the antiepileptic drug carbamazepine prior to temporal lobectomies. An in vitro blood–brain barrier model was then established using primary cell culture derived from the same brain specimens. The pattern of carbamazepine (CBZ) metabolism was evaluated in vitro and ex vivo using high performance liquid chromatography–mass spectroscopy. Accelerated mass spectroscopy was used to identify14 C metabolites deriving from the parent14 C-carbamazepine. Under our experimental conditions carbamazepine levels could not be detected in drug resistant epileptic brain ex situ ; low levels of carbamazepine were detected in the brain side of the in vitro BBB established with endothelial cells derived from the same patients. Four carbamazepine-derived fractions were detected in brain samples in vitro and ex vivo . HPLC-accelerated mass spectroscopy confirmed that these signals derived from14 C-carbamazepine administered as parental drug. Carbamazepine 10, 11 epoxide (CBZ-EPO) and 10, 11-dihydro-10, 11-dihydrooxy-carbamazepine (DiOH-CBZ) were also detected in the fractions analyzed.14 C-enriched fractions were subsequently analyzed by mass spectrometry to reveal micromolar concentrations of quinolinic acid (QA). Remarkably, the disappearance of carbamazepine-epoxide (at a rate of 5% per hour) was comparable to the rate of quinolinic acid production (3% per hour). This suggested that quinolinic acid may be a result of carbamazepine metabolism. Quinolinic acid was not detected in the brain of patients who received antiepileptic drugs other than carbamazepine prior to surgery or in brain endothelial cultures obtained from a control patient. Our data suggest that a drug resistant BBB not only impedes drug access to the brain but may also allow the formation of neurotoxic metabolites. Drugs and their metabolites often produce undesirable effects. These may be due to a number of mechanisms, including biotransformation by P450 enzymes which are not exclusively expressed by hepatocytes but also by endothelial cells in brain from epileptics. The possibility thus exists that the potency of systemically administered central nervous system therapeutics can be modulated by a metabolic blood-brain barrier (BBB). Surgical brain specimens and blood samples (ex vivo) were obtained from drug-resistant epileptic subjects receiving the antiepileptic drug carbamazepine prior to temporal lobectomies. An in vitro blood-brain barrier model was then established using primary cell culture derived from the same brain specimens. The pattern of carbamazepine (CBZ) metabolism was evaluated in vitro and ex vivo using high performance liquid chromatography-mass spectroscopy. Accelerated mass spectroscopy was used to identify (14)C metabolites deriving from the parent (14)C-carbamazepine. Under our experimental conditions carbamazepine levels could not be detected in drug resistant epileptic brain ex situ; low levels of carbamazepine were detected in the brain side of the in vitro BBB established with endothelial cells derived from the same patients. Four carbamazepine-derived fractions were detected in brain samples in vitro and ex vivo. HPLC-accelerated mass spectroscopy confirmed that these signals derived from (14)C-carbamazepine administered as parental drug. Carbamazepine 10, 11 epoxide (CBZ-EPO) and 10, 11-dihydro-10, 11-dihydrooxy-carbamazepine (DiOH-CBZ) were also detected in the fractions analyzed. (14)C-enriched fractions were subsequently analyzed by mass spectrometry to reveal micromolar concentrations of quinolinic acid (QA). Remarkably, the disappearance of carbamazepine-epoxide (at a rate of 5% per hour) was comparable to the rate of quinolinic acid production (3% per hour). This suggested that quinolinic acid may be a result of carbamazepine metabolism. Quinolinic acid was not detected in the brain of patients who received antiepileptic drugs other than carbamazepine prior to surgery or in brain endothelial cultures obtained from a control patient. Our data suggest that a drug resistant BBB not only impedes drug access to the brain but may also allow the formation of neurotoxic metabolites. Drugs and their metabolites often produce undesirable effects. These may be due to a number of mechanisms, including biotransformation by P450 enzymes which are not exclusively expressed by hepatocytes but also by endothelial cells in brain from epileptics. The possibility thus exists that the potency of systemically administered central nervous system therapeutics can be modulated by a metabolic bloodabrain barrier (BBB). |
| Author | Hossain, Mohammed Rasmussen, Peter Janigro, Damir Yang, Hu Alexopoulos, Andreas V. Gonzalez-Martinez, Jorge Ghosh, Chaitali Marchi, Nicola |
| AuthorAffiliation | c Department of Neurological Surgery, Cleveland Clinic Foundation, Cleveland, OH, USA d Department of Cell Biology, Cleveland Clinic Foundation, Cleveland, OH, USA f Department of Biomedical Engineering, School of Engineering, Virginia Commonwealth University, Richmond, VA, USA e Epilepsy Center, Cleveland Clinic Foundation, Cleveland, OH, USA g Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA a Cerebrovascular Research, Cleveland Clinic Foundation, Cleveland, OH, USA b Department of Molecular Medicine, Cleveland Clinic Foundation, Cleveland, OH, USA |
| AuthorAffiliation_xml | – name: d Department of Cell Biology, Cleveland Clinic Foundation, Cleveland, OH, USA – name: f Department of Biomedical Engineering, School of Engineering, Virginia Commonwealth University, Richmond, VA, USA – name: g Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA – name: c Department of Neurological Surgery, Cleveland Clinic Foundation, Cleveland, OH, USA – name: e Epilepsy Center, Cleveland Clinic Foundation, Cleveland, OH, USA – name: a Cerebrovascular Research, Cleveland Clinic Foundation, Cleveland, OH, USA – name: b Department of Molecular Medicine, Cleveland Clinic Foundation, Cleveland, OH, USA |
| Author_xml | – sequence: 1 givenname: Chaitali surname: Ghosh fullname: Ghosh, Chaitali organization: Cerebrovascular Research, Cleveland Clinic Foundation, Cleveland, OH, USA – sequence: 2 givenname: Nicola surname: Marchi fullname: Marchi, Nicola email: marchin@ccf.org organization: Cerebrovascular Research, Cleveland Clinic Foundation, Cleveland, OH, USA – sequence: 3 givenname: Mohammed surname: Hossain fullname: Hossain, Mohammed organization: Cerebrovascular Research, Cleveland Clinic Foundation, Cleveland, OH, USA – sequence: 4 givenname: Peter surname: Rasmussen fullname: Rasmussen, Peter organization: Department of Neurological Surgery, Cleveland Clinic Foundation, Cleveland, OH, USA – sequence: 5 givenname: Andreas V. surname: Alexopoulos fullname: Alexopoulos, Andreas V. organization: Epilepsy Center, Cleveland Clinic Foundation, Cleveland, OH, USA – sequence: 6 givenname: Jorge surname: Gonzalez-Martinez fullname: Gonzalez-Martinez, Jorge organization: Department of Neurological Surgery, Cleveland Clinic Foundation, Cleveland, OH, USA – sequence: 7 givenname: Hu surname: Yang fullname: Yang, Hu organization: Department of Biomedical Engineering, School of Engineering, Virginia Commonwealth University, Richmond, VA, USA – sequence: 8 givenname: Damir surname: Janigro fullname: Janigro, Damir email: janigrd@ccf.org organization: Cerebrovascular Research, Cleveland Clinic Foundation, Cleveland, OH, USA |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/22426401$$D View this record in MEDLINE/PubMed |
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| Keywords | Neurotoxicity In vitro models Tissue engineering Drug metabolism Drug delivery Drug resistance Pharmacokinetics Carbamazepine Blood–brain barrier Pharmacogenomics |
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| PublicationTitle | Neurobiology of disease |
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| SubjectTerms | Adult Anticonvulsants - metabolism Biotransformation Blood-brain barrier Brain Brain Chemistry Carbamazepine Carbamazepine - metabolism Central nervous system Child Chromatography, High Pressure Liquid Convulsants - metabolism Drug delivery Drug metabolism Drug Resistance Drugs Endothelial cells Endothelial Cells - drug effects Enzymes Epilepsy Epilepsy - chemically induced Epilepsy - metabolism Epilepsy, Temporal Lobe - drug therapy Epilepsy, Temporal Lobe - metabolism Epilepsy, Temporal Lobe - surgery Female Hepatocytes Humans In vitro models Male Mass Spectrometry Metabolites Middle Aged Models, Neurological Nervous system Neurology Neurotoxicity Pharmacogenomics Pharmacokinetics Primary Cell Culture Quinolinic acid Quinolinic Acid - chemistry Quinolinic Acid - metabolism Quinolinic Acid - pharmacology Reproducibility of Results Tissue engineering |
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| Title | A pro-convulsive carbamazepine metabolite: Quinolinic acid in drug resistant epileptic human brain |
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