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.
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ABSTRACT: The aim of the study was to report a concentration-dependently biphasic effect of verapamil (VER) on the transport of phenobarbital (PB) across the blood-brain barrier (BBB) in vitro and in vivo. The uptake of PB by rat brain microvessel endothelial cells (rBMECs) and transport of PB across the rBMEC monolayer from apical to basolateral and basolateral to apical were evaluated in the presence of VER. The effect of VER on PB pharmacological activity on the central nervous system (CNS) and brain distribution of PB in mice were further investigated. The results showed that VER regulated the uptake of PB by rBMECs in a concentration-dependently biphasic manner. The uptake of PB by rBMECs was decreased by low concentrations of VER (1-25 μΜ), but increased by high concentrations of VER (50-300 μM). The biphasic regulation was also observed in transport experiment. In vivo studies showed that VER altered the pharmacological effect of PB on CNS and brain concentration of PB in a biphasic manner. In contrast to low doses of VER (0.125-0.5 mg/kg) that shortened the duration time of PB-induced loss of the righting reflex, high doses of VER (2-4 mg/kg) prolonged the duration time. Further study demonstrated that brain concentration of PB was decreased by 0.125 mg/kg VER, but increased by 2 mg/kg VER. The concentration-dependently biphasic regulation was also confirmed in the uptake of rhodamine 123 by rBMECs. Our results suggested that VER may regulate the transport of PB across BBB in a concentration-dependently biphasic manner and the biphasic regulation may be involved in P-gp function.Archiv für Experimentelle Pathologie und Pharmakologie 02/2011; 383(4):393-402. · 2.15 Impact Factor
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ABSTRACT: To investigate the changes of expression and function of P-glycoprotein (P-GP) in cerebral cortex, hippocampus, liver, intestinal mucosa and kidney of streptozocin-induced diabetic rats. Diabetic rats were prepared via a single dose of streptozocin (65 mg/kg, ip). Abcb1/P-GP mRNA and protein expression levels in tissues were evaluated using quantitative real time polymerase chain reaction (QRT-PCR) analysis and Western blot, respectively. P-GP function was investigated via measuring tissue-to-plasma concentration ratios and body fluid excretion percentages of rhodamine 123. In 5- and 8-week diabetic rats, Abcb1a mRNA levels were significantly decreased in cerebral cortices and intestinal mucosa, but dramatically increased in hippocampus and kidney. In liver, the level was increased in 5-week diabetic rats, and decreased in 8-week diabetic rats. Abcb1b mRNA levels were increased in cerebral cortex, hippocampus and kidney, but reduced in liver and intestinal mucosa in the diabetic rats. Western blot results were in accordance with the alterations of Abcb1a mRNA levels in most tissues examined. P-GP activity was markedly decreased in most tissues of diabetic rats, except kidney tissues. Alterations in the expression and function of Abcb1/P-GP under diabetic conditions are tissue specific, Abcb1 specific and diabetic duration-dependent.Acta Pharmacologica Sinica 06/2011; 32(7):956-66. · 2.35 Impact Factor
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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