Avaliação da influência da glicoproteína-p na farmacocinética de fármacos antiepilépticos em ratos

• Ano de defesa: 2021
• Autor(a) principal: Placido, Rodrigo Vicentino
• Orientador(a): Marques, Vanessa Bergamin Boralli
• Banca de defesa: Godoy, Lívea Dornela, Antunes, Natalícia De Jesus, Leitão, Silvia Graciela Ruginsk, Figueiredo, Eduardo Costa De
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Federal de Alfenas
• Programa de Pós-Graduação: Programa de Pós-Graduação em Ciências Farmacêuticas
• Departamento: Faculdade de Ciências Farmacêuticas
• País: Brasil
• Palavras-chave em Português: Epilepsia; Transportadores; Antiepilépticos; Farmacocinética
• Área do conhecimento CNPq: CIENCIAS DA SAUDE::FARMACIA
• Link de acesso: https://repositorio.unifal-mg.edu.br/handle/123456789/1880

Epilepsy is a pathology characterized by recurrent seizures that occur as a result of excessive electrical discharges that affect brain cells. The disease has a worldwide incidence, affecting about fifty million people, being more prevalent in developing countries. About 30% of these patients do not respond to treatment, which may be due to the influence of transporters on the pharmacokinetics of antiepileptic drugs. The main efflux transporter responsible for this resistance is the P-glycoprotein (P-gp), especially present in the blood- brain barrier. Since antiepileptic drugs are P-gp substrates, they undergo efflux action, causing pharmacokinetic changes, or subtherapeutic concentrations in the central nervous system (CNS), since this is their main site of pharmacological action. Given the above, the present study aimed to evaluate the pharmacokinetics of antiepileptic drugs and fexofenadine, comparing control animals and epileptic rats induced by the pilocarpine model. The use of P-gp inhibitors (verapamil), as a possible therapeutic alternative, was also evaluated. For the group treated with fexofenadine with P-gp inhibitor, it was observed in the AUC 0-3h that there was a reduction in the control group (223.9 vs. 154.9ng.h/mL) and in the epileptic group (136.4 vs. 71.3ng.h/mL). For carbamazepine pharmacokinetics, no statistical differences were observed between the control and epileptic groups, nor in the use of P-gp inhibitor, which can be explained by the fact that carbamazepine is not an ideal substrate for P- gp in rats. For the pharmacokinetics of phenobarbital, an increase in AUC 0- was observed in the epileptic group compared to the control (20804 vs. 8789.5ng.h/mL), however, when administering the P-gp inhibitor to the epileptic group, this parameter was reduced (20804 vs. 11713ng.h/mL). For the pharmacokinetics of phenytoin, an increase in AUC 0- was also observed for the epileptic group compared to the control (9860.2 vs. 2393.4ng.h/mL) and a reduction in AUC0- when administering the inhibitor (9860.2 vs. 5823.9ng.h/mL). The increase in plasma availability reflects the reduction in drug entry into the CNS, due to increased P-gp expression, directly related to the induction of epilepsy and pilocarpine in the blood-brain barrier, causing a greater amount of drug in the circulation. However, when the inhibitor is administered, the efflux activity of the transporter is blocked, allowing greater distribution of the drug and thus reducing its plasma concentration. These results point to the use of P-gp inhibitor as a promising alternative for the treatment of refractory epilepsy; it is noteworthy that treatment refractoriness is a complex and multifactorial mechanism.