Evaluation of carbamazepine pharmacokinetic profiles in mice with kainic acid-induced acute seizures.
The purpose of the present study was to evaluate the effect of kainic acid (KA)-induced acute seizures on the pharmacokinetic profiles of antiepileptic drug, carbamazepine (CBZ) in mice. Experimental acute seizure in mice was induced by intraperitoneal injection of KA (30 mg/kg), and mice were provided for experiments after 48 h of KA treatment. The portal plasma concentrations of CBZ and its metabolite carbamazepine-10,11-epoxide (CBZ-epo) had trends to decrease as compared to the control mice, whereas the brain CBZ and CBZ-epo concentrations was actually lower in KA treated mice. On the other hand, the exsorption of CBZ from blood to the intestinal lumen via P-glycoprotein (P-gp) in KA treated-mice was significantly increased in parallel with that of Rhodamine-123 (Rho123), a P-gp substrate. Western blotting analysis for intestinal and cerebral P-gp showed that the P-gp expression was induced in the KA-treated mice. The apparent brain-to-plasma concentration ratio (Kp) of CBZ in the KA-treated mice showed significant decrease but that of CBZ-epo did not. Moreover, in the KA-treated mice, the percentage of protein binding was significantly increased, and found to be an inverse proportion in the relationship between the Kp and protein binding of CBZ. In conclusion, the mechanism responsible for a decreased brain CBZ concentration in the KA-induced seizure mice is based on the up-regulation of P-gp function in tissues and plasma protein binding of CBZ.
Nishimura
Asako
A
Department of Biopharmaceutics, Faculty of Pharmaceutical Sciences, Doshisha Women's College of Liberal Arts, Kodo Kyotanabe, Kyoto 610-0395, Japan.
Honda
Naoki
N
Sugioka
Nobuyuki
N
Takada
Kanji
K
Shibata
Nobuhito
N
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000208:Acute Disease; D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics* / Q000494:pharmacology*; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002220:Carbamazepine / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004396:Coloring Agents; D003627:Data Interpretation, Statistical; D004351:Drug Resistance; D018690:Excitatory Amino Acid Agonists; D007262:Infusions, Intravenous; D007413:Intestinal Mucosa / Q000378:metabolism; D007608:Kainic Acid; D008297:Male; D051379:Mice; D010477:Perfusion; D011485:Protein Binding; D012015:Reference Standards; D020112:Rhodamine 123; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism*; D012996:Solutions
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000927:Anticonvulsants; D004396:Coloring Agents; D018690:Excitatory Amino Acid Agonists; D012996:Solutions; D020112:Rhodamine 123; D002220:Carbamazepine; D007608:Kainic Acid