Evaluation of carbamazepine pharmacokinetic profiles in mice with kainic acid-induced acute seizures.
ABSTRACT 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.
[show abstract] [hide abstract]
ABSTRACT: Epilepsy is the most common serious chronic neurological disorder. Current data show that one-third of patients do not respond to anti-epileptic drugs (AEDs). Most non-responsive epilepsy patients are resistant to several, often all, AEDs, even though the drugs differ from each other in pharmacokinetics, mechanisms of action, and interaction potential. The mechanisms underlying drug resistance of epilepsy patients are still not clear. In recent years, one of the potential mechanisms interesting researchers is over-expression of P-glycoprotein (P-gp, also known as ABCB1 or MDR1) in endothelial cells of the blood-brain barrier (BBB) in epilepsy patients. P-gp plays a central role in drug absorption and distribution in many organisms. The expression of P-gp is greater in drug-resistant than in drug-responsive patients. Some studies also indicate that several AEDs are substrates or inhibitors of P-gp, implying that P-gp may play an important role in drug resistance in refractory epilepsy. In this article, we review the clinical and laboratory evidence that P-gp expression is increased in epileptic brain tissues and that AEDs are substrates of P-gp in vitro and in vivo. We discuss criteria for identifying the substrate status of AEDs and use structure-activity relationship (SAR) models to predict which AEDs act as P-gp substrates.Advanced drug delivery reviews 12/2011; 64(10):930-42. · 11.96 Impact Factor