Nimodipine restores the altered hippocampal phenytoin pharmacokinetics in a refractory epileptic model
The present work was undertaken to examine the central pharmacokinetics of phenytoin (PHT) in an experimental model of epilepsy, induced by administration of 3-mercaptopropionic acid (MP), and possible participation of P-glycoprotein in this model of epilepsy. Repeated seizures were induced in male...
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| Published in: | Neuroscience letters Vol. 413; no. 2; pp. 168 - 172 |
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| Main Authors: | , , , , , , , |
| Format: | Journal Article |
| Language: | English |
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| Abstract | The present work was undertaken to examine the central pharmacokinetics of phenytoin (PHT) in an experimental model of epilepsy, induced by administration of 3-mercaptopropionic acid (MP), and possible participation of P-glycoprotein in this model of epilepsy. Repeated seizures were induced in male Wistar rats by injection of 3-MP (45
mg
kg
−1, i.p.) during 10 days. Control rats (C) were injected with saline solution. In order to monitor extracellular PHT levels, either a shunt microdialysis probe or a concentric probe was inserted into carotid artery or hippocampus, respectively. All animals were administered with PHT (30
mg
kg
−1, i.v.) 30
min after intraperitoneal administration of vehicle (V) or nimodipine (NIMO, 2
mg
kg
−1). No differences were found in PHT plasma levels comparing all experimental groups. In pre-treated rats with V, hippocampal PHT concentrations were lower in MP (maximal concentration,
C
max: 2.7
±
0.3
μg
ml
−1,
p
<
0.05 versus C rats) than in C animals (
C
max: 5.3
±
0.9
μg
ml
−1). Control rats pre-treated with NIMO showed similar results (
C
max: 4.5
±
0.8
μg
ml
−1) than those pre-treated with V. NIMO pre-treatment of MP rats showed higher PHT concentrations (
C
max: 6.8
±
1.0
μg
ml
−1,
p
<
0.05) when compared with V pre-treated MP group. Our results indicate that central pharmacokinetics of PHT is altered in MP epileptic rats. The effect of NIMO on hippocampal concentrations of PHT suggests that P-glycoprotein has a role in reduced central bioavailability of PHT in our epileptic refractory model. |
|---|---|
| AbstractList | The present work was undertaken to examine the central pharmacokinetics of phenytoin (PHT) in an experimental model of epilepsy, induced by administration of 3-mercaptopropionic acid (MP), and possible participation of P-glycoprotein in this model of epilepsy. Repeated seizures were induced in male Wistar rats by injection of 3-MP (45
mg
kg
−1, i.p.) during 10 days. Control rats (C) were injected with saline solution. In order to monitor extracellular PHT levels, either a shunt microdialysis probe or a concentric probe was inserted into carotid artery or hippocampus, respectively. All animals were administered with PHT (30
mg
kg
−1, i.v.) 30
min after intraperitoneal administration of vehicle (V) or nimodipine (NIMO, 2
mg
kg
−1). No differences were found in PHT plasma levels comparing all experimental groups. In pre-treated rats with V, hippocampal PHT concentrations were lower in MP (maximal concentration,
C
max: 2.7
±
0.3
μg
ml
−1,
p
<
0.05 versus C rats) than in C animals (
C
max: 5.3
±
0.9
μg
ml
−1). Control rats pre-treated with NIMO showed similar results (
C
max: 4.5
±
0.8
μg
ml
−1) than those pre-treated with V. NIMO pre-treatment of MP rats showed higher PHT concentrations (
C
max: 6.8
±
1.0
μg
ml
−1,
p
<
0.05) when compared with V pre-treated MP group. Our results indicate that central pharmacokinetics of PHT is altered in MP epileptic rats. The effect of NIMO on hippocampal concentrations of PHT suggests that P-glycoprotein has a role in reduced central bioavailability of PHT in our epileptic refractory model. The present work was undertaken to examine the central pharmacokinetics of phenytoin (PHT) in an experimental model of epilepsy, induced by administration of 3-mercaptopropionic acid (MP), and possible participation of P-glycoprotein in this model of epilepsy. Repeated seizures were induced in male Wistar rats by injection of 3-MP (45 mg kg(-1), i.p.) during 10 days. Control rats (C) were injected with saline solution. In order to monitor extracellular PHT levels, either a shunt microdialysis probe or a concentric probe was inserted into carotid artery or hippocampus, respectively. All animals were administered with PHT (30 mg kg(-1), i.v.) 30 min after intraperitoneal administration of vehicle (V) or nimodipine (NIMO, 2 mg kg(-1)). No differences were found in PHT plasma levels comparing all experimental groups. In pre-treated rats with V, hippocampal PHT concentrations were lower in MP (maximal concentration, C(max): 2.7+/-0.3 microg ml(-1), p<0.05 versus C rats) than in C animals (C(max): 5.3+/-0.9 microg ml(-1)). Control rats pre-treated with NIMO showed similar results (C(max): 4.5+/-0.8 microg ml(-1)) than those pre-treated with V. NIMO pre-treatment of MP rats showed higher PHT concentrations (C(max): 6.8+/-1.0 microg ml(-1), p<0.05) when compared with V pre-treated MP group. Our results indicate that central pharmacokinetics of PHT is altered in MP epileptic rats. The effect of NIMO on hippocampal concentrations of PHT suggests that P-glycoprotein has a role in reduced central bioavailability of PHT in our epileptic refractory model. |
| Author | Auzmendi, Jerónimo Lazarowski, Alberto Gonzalez, Nélida N. Bramuglia, Guillermo F. Opezzo, Javier A.W. Taira, Carlos A. Girardi, Elena Höcht, Christian |
| Author_xml | – sequence: 1 givenname: Christian surname: Höcht fullname: Höcht, Christian email: chocht@ffyb.uba.ar organization: Cátedra de Farmacología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956, (C1113AAD) Buenos Aires, Argentina – sequence: 2 givenname: Alberto surname: Lazarowski fullname: Lazarowski, Alberto organization: Instituto de Biología Celular y Neurociencia “Prof. Eduardo De Robertis”, Facultad de Medicina, Universidad de Buenos Aires, Argentina – sequence: 3 givenname: Nélida N. surname: Gonzalez fullname: Gonzalez, Nélida N. organization: Instituto de Biología Celular y Neurociencia “Prof. Eduardo De Robertis”, Facultad de Medicina, Universidad de Buenos Aires, Argentina – sequence: 4 givenname: Jerónimo surname: Auzmendi fullname: Auzmendi, Jerónimo organization: Instituto de Biología Celular y Neurociencia “Prof. Eduardo De Robertis”, Facultad de Medicina, Universidad de Buenos Aires, Argentina – sequence: 5 givenname: Javier A.W. surname: Opezzo fullname: Opezzo, Javier A.W. organization: Cátedra de Farmacología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956, (C1113AAD) Buenos Aires, Argentina – sequence: 6 givenname: Guillermo F. surname: Bramuglia fullname: Bramuglia, Guillermo F. organization: Cátedra de Farmacología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956, (C1113AAD) Buenos Aires, Argentina – sequence: 7 givenname: Carlos A. surname: Taira fullname: Taira, Carlos A. organization: Cátedra de Farmacología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956, (C1113AAD) Buenos Aires, Argentina – sequence: 8 givenname: Elena surname: Girardi fullname: Girardi, Elena organization: Instituto de Biología Celular y Neurociencia “Prof. Eduardo De Robertis”, Facultad de Medicina, Universidad de Buenos Aires, Argentina |
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| Keywords | P-glycoprotein Refractory epilepsy Microdialysis Nimodipine Phenytoin Nervous system diseases Epilepsy Central nervous system Glycoprotein Anticonvulsant Cerebral disorder Central nervous system disease Models Hippocampus |
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| SubjectTerms | 3-Mercaptopropionic Acid Animals Anticonvulsants - agonists Anticonvulsants - pharmacokinetics ATP-Binding Cassette, Sub-Family B, Member 1 - drug effects ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism Biological and medical sciences Calcium Channel Blockers - pharmacology Calcium Channel Blockers - therapeutic use Convulsants Disease Models, Animal Drug Resistance - drug effects Drug Resistance - physiology Epilepsy - chemically induced Epilepsy - drug therapy Epilepsy - metabolism Extracellular Fluid - drug effects Extracellular Fluid - metabolism Fundamental and applied biological sciences. Psychology Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy Hippocampus - drug effects Hippocampus - metabolism Hippocampus - physiopathology Male Medical sciences Microdialysis Nervous system (semeiology, syndromes) Neurology Nimodipine Nimodipine - pharmacology Nimodipine - therapeutic use P-glycoprotein Phenytoin Phenytoin - agonists Phenytoin - pharmacokinetics Rats Rats, Wistar Refractory epilepsy Vertebrates: nervous system and sense organs |
| Title | Nimodipine restores the altered hippocampal phenytoin pharmacokinetics in a refractory epileptic model |
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