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Impact of P-glycoprotein on the efficiency of carbamazepine transport across the blood-brain barrierтезисы доклада Тезисы
- Авторы: Zybina A., Kulichenkova K., Abbasova K.
- Сборник: 29th ECNP Congress - Vienna 2016
- Тезисы
- Год издания: 2016
- Место издания: 3508 AK Utrecht The Netherlands The Netherlands
- Первая страница: P.1.d.006
- Аннотация: Purpose: Antiepileptic drugs (AEDs) are most commonly used in treatment of epilepsy. Though many new antiepileptic drugs have been developed in the recent decades, drug resistance remains a major problem. About 30% of patients are refractory to treatment with more than one antiepileptic drug [1]. Mechanisms underlying AEDs resistance are not yet completely understood. Overexpression of the multidrug efflux transporter P-glycoprotein (P-gp) and other ATP-Binding Cassette (ABC) transporters in the blood–brain barrier (BBB) is thought to be involved in pharmacoresistance in epilepsy by extruding AEDs from epileptic site [2]. P-gp has been shown to be a transporter for major AEDs. The transport of AEDs from the brain back into blood vessels causes lower brain concentration of AEDs. Carbamazepine (CBZ) is one of the first line AEDs widely used in the treatment of epilepsy, sharing a common mode of action by exerting voltage-dependent blockade of neuronal voltage-gated sodium channels. There is controversial evidence whether CBZ is transported by Pgp. Some researchers have shown that carbamazepine (CBZ) could increase the expression of P-gp in the rat brain and rat brain microvascular endothelial cells [3]. Conversely, it was shown that CBZ is not a substrate for P-glycoprotein [4]. In this study, we have investigated whether CBZ is a Pgp substrate using isoniazid model. Methods: The study was carried out on adult male Wistar rats (n = 50) weighting 250–300 g. Seizures were induced by the i.p. administration of (INH, 300 mg/kg) in all animals. Rats were divided into four groups: in the first Isoniazid (INH) group (n = 16) they didn't get any AED treatment; second CBZ-30 mg/kg (i.v.) group (n = 10); third CBZ ˗20 mg/kg (i.v.) group (n = 12) and forth group received Verapamil, (selective inhibitor of P-gp) before CBZ ˗20 mg/kg (i.v). (VER, 40 mg/kg) by concomitant administration of CBZ (20 mg/kg). The seizure severity was evaluated using Racine's 5-stage scale. Results: Intravenous. injection of CBZ 30 mg/kg significantly (p < 0.01) decreased duration, intensity and increased latency of INH induced seizures. Efficacy of CBZ 20 mg/kg was significantly lower compared with CBZ 30 mg/kg and didn't show anticonvulsant effect. In contrast to this, concomitant administration VER and CBZ 20 mg/kg significantly (p < 0.01) decreased duration, intensity and increased latency of INH induced seizures compare with INH group. All rats reached 4 or 5 stage after INH application. Qualitative evaluation of BBB permeability in the background of INH and/or CBZ was based on injection of Evans Blue (i.v., 40 mg/kg). Penetration of the dye was evaluated post mortem with fluorescence microscopy of 20 mkm slices. There was found no fluorescence in all experimental groups, and this is an evidence of BBB integrity during the experiment. Conclusion: Our findings demonstrate that multidrug efflux transporter P-glycoprotein at the blood–brain barrier can be a substrate for CBZ or its metabolites. References [1] Kwan, P., Sander, J.W., 2004. The natural history of epilepsy: an epidemiological view. J. Neurol. Neurosurg. Psychiatry 75, 1376—1381. [2] Löscher, W., Potschka, H., 2005. Blood—brain barrier active efflux transporters: ATP-binding cassette gene family. NeuroRx 2, 86—98. [3] Yang, H.W., Liu, H.Y., Liu, X., Zhang, D.M., Liu, Y.C., Liu, X.D., Wang, G.J., Xie, L., 2008. Increased P-glycoprotein function and level after long-term exposure of four antiepileptic drugs to rat brain microvascular endothelial cells in vitro. Neurosci Lett. 434, 299–303. [4] Owen, A., Pirmohamed, M., Tettey, J.N., Morgan, P., Chadwick, D., Park, B.K., 2001. Carbamazepine is not a substrate for P-glycoprotein Br J Clin Pharmacol. 51(4), 345–9.
- Добавил в систему: Аббасова Кенул Расим кызы