Influence of the dual combination of silymarin and (-)-epigallocatechin gallate, natural dietary flavonoids, on the pharmacokinetics of oxcarbazepine in rats. (August 2017)

• Record Type: Journal Article
• Authors: Ferreira, Ana; Rodrigues, Márcio; Marques, Alexandre; Falcão, Amílcar; Alves, Gilberto
• Is Part Of: Food and chemical toxicology. Volume 106:Part A(2017)
• Page Start: 446
• Page End: 454
• Publication Date: 2017-08
• Subjects: (-)-Epigallocatechin gallate -- Licarbazepine -- Oxcarbazepine -- P-glycoprotein -- Pharmacokinetics -- Silymarin; AEDs antiepileptic drugs -- AUC area under the concentration-time curve -- AUC0-t AUC from time zero to the last sampling time -- AUC0-∞ AUC from time zero to infinite -- Clast last quantifiable concentration -- Cmax peak concentration -- CV coefficient of variation -- CYP cytochrome P450 -- DAD diode array detector -- DMSO dimethyl sulfoxide -- HPLC high-performance liquid chromatography -- i.p. intraperitoneal -- kel apparent terminal rate constant -- LIC licarbazepine -- LLOQ lower limit of quantification -- MRT mean residence time -- OXC oxcarbazepine -- P-gp P-glycoprotein -- QC quality control -- SEM standard error of the mean -- t1/2el apparent terminal elimination half-life -- tmax time to reach Cmax; Toxicology -- Periodicals; Food poisoning -- Periodicals; Food Poisoning -- Periodicals; Toxicology -- Periodicals; Toxicologie -- Périodiques; Intoxications alimentaires -- Périodiques; Food poisoning; Toxicology; Periodicals; Electronic journals; 615.9
• DOI: 10.1016/j.fct.2017.06.015
• Languages: English
• ISSNs: 0278-6915

Abstract

Abstract: Considering the potential of flavonoids in reversing the P-glycoprotein (P-gp)–mediated multidrug resistance, this work aimed to assess the combined effects of silymarin and (-)-epigallocatechin gallate (EPG) on the pharmacokinetics of the P-gp substrates oxcarbazepine (OXC) and licarbazepine (LIC). Rats were pre-treated intraperitoneally with silymarin (25 mg/kg), EPG (25 mg/kg), silymarin/EPG (12.5/12.5 mg/kg; 6.25/18.75 mg/kg; 18.75/6.25 mg/kg) or verapamil (25 mg/kg, reference P-gp inhibitor) before the intraperitoneal administration of OXC (50 mg/kg). Pre-treatment with dual silymarin/EPG combinations originated peak plasma concentrations of OXC and LIC (pharmacologically active metabolite of OXC) similar to those achieved in the presence of verapamil (positive control). Moreover, the effects promoted by silymarin/EPG combinations on the magnitude of systemic drug exposure to OXC and LIC were also reflected in the corresponding drug levels attained in the brain (biophase). These findings evidence the synergistic effect of silymarin and EPG in enhancing the degree of systemic exposure to OXC and LIC in rats, which occurred in a comparable extent to that observed with verapamil. Hence, our findings support the combination of flavonoid-type P-gp inhibitors and P-gp substrate antiepileptic drugs as a potential therapeutic strategy for the management of pharmacoresistant epilepsy. Graphical abstract: Highlights: Natural dietary flavonoids silymarin and (-)-epigallocatechin gallate as in vivo P-gp inhibitors. Flavonoids as reversing agents of the pharmacoresistance in epilepsy. Pre-administration of flavonoid combinations significantly increased the Cmax of oxcarbazepine.