Evaluation of the Pharmacokinetic Interactions of Maytenus ilicifolia Mart. ex Reiss Extracts on Drug Intestinal Permeability and Hepatic Metabolism

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Abstract
Maytenus ilicifolia Mart. ex Reiss is a plant native to South America, popularly used in the treatment of gastric disorders. The increase in the consumption of herbal products associated with conventional medications demands attention for the potential risks of interactions. The aim of the study was to evaluate potential pharmacokinetic interactions due to coadministration of M. ilicifolia extracts with drug substrates of P-glycoprotein (P-gp) and cytochrome P450 3A4 isoform (CYP3A4). Five extracts of M. ilicifolia were prepared, and the contents of the main secondary metabolites were determined. A high-performance liquid chromatography (HPLC) method was developed for the simultaneous quantitation of midazolam, nifedipine, and their respective metabolites and applied to assess the potential of M. ilicifolia extracts on hepatic metabolism mediated by the CYP3A4 enzyme. The influence of the extracts on the intestinal permeability of fexofenadine was evaluated by determining P-gp activity, using a Caco-2 cell model. The extracts were characterized in terms of total phenolic (1.77–11.46%), tannin (1.67–3.36%), and flavonoid (0.21–2.64%). The hydroacetonic extract (HAE1) exhibited a remaining activity (%RA) of 50.1% for the 1-hydroxylation of midazolam and 40.1% for the oxidation of nifedipine, indicating moderate inhibition of CYP3A4. HAE1 reduced the fexofenadine efflux ratio to an extent similar to that of verapamil (IC50 = 20.42 μg/mL), suggesting an inhibitory effect on the P-gp activity. The extracts demonstrated the potential to inhibit both CYP3A4 and P-gp. Therefore, coadministration of M. ilicifolia-based preparations may potentially alter the pharmacokinetics of drugs that are substrates of these systems.
Funding Information
  • Funda??o de Amparo ? Pesquisa do Estado de Minas Gerais (APQ-01104-24)
  • Pr?-Reitoria de Pesquisa, Universidade Federal de Minas Gerais
  • Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico (306186/2021, 444.467/2023-8, 465571/2014-0)
  • Funda??o de Amparo ? Pesquisa do Estado de S?o Paulo (2014/50945-4, 2018/07534-4, 2021/10098-4)
  • Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior

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