Differential hippocampal pharmacokinetics of phenobarbital and carbamazepine in repetitive seizures induced by 3-mercaptopropionic acid.
Previous evidence has shown that chronic 3-mercaptopropionic acid (MP) administration induced brain P-glycoprotein (P-gp) overexpression altering target site accumulation of phenytoin. The aim of the present work was to assess the involvement of P-glycoprotein in carbamazepine and phenobarbital hippocampal pharmacokinetics in an experimental model of epilepsy, induced by repetitive MP administration. Seizures were induced in Wistar rats by injection of MP (45 mg kg(-1), i.p.) during 10 days. Control rats (C) were injected with saline solution. In order to monitor extracellular brain antiepileptic levels, a concentric probe was inserted into the hippocampus. Animals were administered with carbamazepine (10 mg kg(-1), i.v.) or phenobarbital (20 mg kg(-1), i.v.) 30 min after intraperitoneal administration of vehicle or nimodipine (2 mg kg(-1)), a well known P-glycoprotein inhibitor. No differences were found in hippocampal concentrations of carbamazepine comparing all groups. In vehicle pre-treated rats, hippocampal phenobarbital concentrations were lower in MP (maximal concentration, C(max): 6.0+/-0.6 microg ml(-1), p<0.05) than in C animals (C(max): 9.4+/-0.9 microg ml(-1)). Control rats pre-treated with nimodipine showed similar results (C(max): 10.7+/-0.6 microg ml(-1)) than those pre-treated with vehicle. Nimodipine pre-treatment in MP rats enhanced hippocampal phenobarbital concentrations (C(max): 10.2+/-1.0 microg ml(-1), p<0.05) as compared with vehicle pre-treatment. Results of our work suggest that P-glycoprotein (P-gp) overexpression by repetitive seizures induced by MP administration does not modify brain bioavailability of carbamazepine. Conversely, hippocampal levels of phenobarbital are reduced in MP rats with regard to non-epileptic rats, suggesting a potential role of P-gp overexpression in pharmacoresistance to phenobarbital.
Höcht
Christian
C
Cátedra de Farmacología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956, (C1113AAD) Buenos Aires, Argentina. chocht@ffyb.uba.ar
Lazarowski
Alberto
A
Gonzalez
Nélida N
NN
Mayer
Marcos A
MA
Opezzo
Javier A W
JA
Taira
Carlos A
CA
Girardi
Elena
E
D015097:3-Mercaptopropionic Acid; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics*; D002220:Carbamazepine / Q000493:pharmacokinetics*; D004195:Disease Models, Animal; D004827:Epilepsy / Q000139:chemically induced / Q000188:drug therapy; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D017551:Microdialysis; D009553:Nimodipine / Q000494:pharmacology; D010634:Phenobarbital / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy*; D013995:Time
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000927:Anticonvulsants; D002220:Carbamazepine; D009553:Nimodipine; D015097:3-Mercaptopropionic Acid; D010634:Phenobarbital