Efeito de produtos naturais amazônicos na farmacocinética de marcadores da atividade enzimática do citocromo P450

Abstract

The use of natural products for the treatment of diseases is increasing among people and, over the years, it has been shown that certain plants may present dangerous substances, particularly when associated with other drugs. Therapeutic failure or intoxication of these associations are likely to occur and currently caught great interest from the scientific community due to serious problems related to this process. The majority of the interactions are based on interference in the metabolism step through induction or inhibition of key enzymes. In this study, two species, Paullinia cupana (guarana) and Eugenia punicifolia (pedra-ume-caá) were selected, for the evaluation of its effects on the pharmacokinetics of markers of enzyme activity of cytochrome P450 in rats since they are widely used by the Amazonian population and with great biotechnological potential. To ensure the quality of Raw Material Plant (RMP), quality control tests previously described by the Brazilian Pharmacopoeia were performed, such as water and extractives content, presence of impurities, among others. In relation to in-vivo experiments, animals were pretreated with the extract of guarana seeds (14 days) or extract of pedra-ume-caá (single dose), and immediately after treatment, received theophylline and midazolam, respectively. Blood samples were collected at pre-determined times through a cannula inserted into the left carotid artery. Theophylline and midazolam plasma levels were quantified using previously validated methods employing HPLC-DAD technique, for determination of pharmacokinetic parameters such as plasma half-life, clearance, area under the curve, among others. Analysis of variance was applied to check for differences between groups by analysis of pharmacokinetic parameters obtained and the level of significance was set at 5% (p <0.05). The results for these species as quality control are in accordance with the parameters described in the Brazilian Pharmacopoeia, ensuring the quality of the constituents present in the extracts and safety in handling them. In pharmacokinetic analysis, a single dose of the extract E. punicifolia showed significant change in the kinetics of midazolam, indicating a probable enzyme inhibition, and may interfere in the pharmacological response of drugs metabolized by CYP3A. The subchronic treatment with the solution of P. cupana showed a significant change in the kinetics of theophylline, indicating a probable enzyme induction, and may interfere with the pharmacological response of drugs metabolized by CYP1A2. Thus, this study demonstrated changes in the pharmacokinetics of drugs in rats caused by the use of natural products and, therefore, additional studies should be conducted to elucidate the phenomenon observed.