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Evaluation of the Effects of Maytenus ilicifolia on the Activities of Cytochrome P450 3A and P-Glycoprotein

Author(s):

Sara Batista do Nascimento, Mariana de Lima Nascimento, Laís Lobato de Araújo, Flávio Martins de Oliveira, Maria do Carmo Vieira, Joaquim Maurício Duarte-Almeida, João Máximo Siqueira, Isabela da Costa César, Hartmut Derendorf and Whocely Victor de Castro*   Pages 1 - 10 ( 10 )

Abstract:


Background: Maytenus ilicifolia is a Brazilian popular medicine commonly used to treat ulcer and gastritis. Despite of the absence of toxicity regarding its consumption, possible interactions when co-administrated with conventional drugs are unknown.

Objective: This study aimed to evaluate the effects of M. ilicifolia extracts on Cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp) activities.

Method: The extracts were obtained by infusion (MI) or turbo-extraction using hydroacetonic solvent (MT70). The content of polyphenols in each extract was determined. To assess the modulation of M. ilicifolia on P-gp activity, the uptake of fexofenadine (FEX) by Caco-2 cells was investigated in the absence or presence of MI or MT70. The effect on CYP3A activity was evaluated by the co-administration of midazolam (MDZ) with each extract in male Wistar rats. The pharmacokinetic parameters of the drug were determined and compared with those from control group. The content of total phenolic compounds, tannins and flavonoids on MT70 extract was about the double of that found in MI.

Results: In the presence of the extracts the uptake of the P-gp marker (FEX) by Caco-2 cells increased from 1.7 ± 0.4 ng.mg-1 protein (control) to 3.5 ± 0.2 ng.mg-1 protein (MI) and 4.4 ± 0.5 ng.mg-1 protein (MT70), respectively. When orally co-administrated with MDZ (substrate of CYP3A), the extracts augmented the AUC(0-∞) (Control: 911.7 ± 215.7 ng.h.mL-1; MI: 1947 ± 554.3 ng.h.mL-1; MT70: 2219.0 ± 506.3 ng.h.mL-1) and the Cmax (Control: 407.7 ± 90.4 ng.mL-1; MI: 1770.5 ± 764.5 ng.mL-1; MT70: 1987.2 ± 544.9 ng.mL-1) of the drug in rats indicating a 50% reduction of the oral Cl. No effect was observed when midazolam was given intravenously.

Conclusion: The results suggest that M. ilicifolia can inhibit the intestinal metabolism and transport of drugs mediated by CYP3A and P-gp, respectively, however, involvement of other transporters and the clinical relevance of such interaction still need to be clarified.

Keywords:

Maytenus ilicifolia, P-glycoprotein, Cytochrome P4503A, herbal-drug interaction, MT70, Caco-2.

Affiliation:

Federal University of São João del-Rei, Av. Sebastião Gonçalves Coelho, 400, Campus Centro-Oeste, Chanadour, Divinópolis-MG, Federal University of São João del-Rei, Av. Sebastião Gonçalves Coelho, 400, Campus Centro-Oeste, Chanadour, Divinópolis-MG, Federal University of São João del-Rei, Av. Sebastião Gonçalves Coelho, 400, Campus Centro-Oeste, Chanadour, Divinópolis-MG, Federal University of São João del-Rei, Av. Sebastião Gonçalves Coelho, 400, Campus Centro-Oeste, Chanadour, Divinópolis-MG, Federal University of Grande Dourados R. João Rosa Góes, 1761 - Vila Progresso, Dourados - MS, Federal University of São João del-Rei, Av. Sebastião Gonçalves Coelho, 400, Campus Centro-Oeste, Chanadour, Divinópolis-MG, Federal University of São João del-Rei, Av. Sebastião Gonçalves Coelho, 400, Campus Centro-Oeste, Chanadour, Divinópolis-MG, Federal University of Grande Dourados R. João Rosa Góes, 1761 - Vila Progresso, Dourados - MS, Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL - PO Box 100494 , Federal University of São João del-Rei, Av. Sebastião Gonçalves Coelho, 400, Campus Centro-Oeste, Chanadour, Divinópolis-MG



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