评价卫矛醇提物对细胞色素 P4503A 和 P-糖蛋白活性的影响。

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

机构信息

Federal University of Sao Joao del-Rei, Av. Sebastiao Goncalves Coelho, 400, Campus Centro-Oeste, Chanadour, Divinopolis-MG, CEP: 35501-296, Brazil.

Federal University of Minas Gerais, Av. Presidente Antonio Carlos, 667, Campus Pampulha, Belo Horizonte-MG, CEP: 31270-901, Brazil.

出版信息

Curr Drug Metab. 2020;21(4):281-290. doi: 10.2174/1389200221666200512112718.

DOI:10.2174/1389200221666200512112718

PMID:32394829

Abstract

BACKGROUND

Maytenus ilicifolia is a Brazilian popular medicine commonly used to treat ulcer and gastritis. Despite 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.

METHODS

The extracts were obtained by infusion (MI) or turbo-extraction using hydro-acetonic 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 the control group. The content of total phenolic compounds, tannins, and flavonoids on MT70 extract was about 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, the involvement of other transporters and the clinical relevance of such interaction still need to be clarified.

摘要

背景

五月茶 Maytenus ilicifolia 是一种巴西常用民间药物，用于治疗溃疡和胃炎。尽管其食用安全性良好，但与传统药物同时使用时，其对细胞色素 P450 3A（CYP3A）和 P-糖蛋白（P-gp）的潜在影响尚不清楚。

目的

本研究旨在评估五月茶的提取物对细胞色素 P450 3A（CYP3A）和 P-糖蛋白（P-gp）活性的影响。

方法

采用水-乙酸乙酯溶剂进行渗滤提取（MI）或涡轮提取（MT70），得到五月茶提取物。测定各提取物中多酚类化合物的含量。为了评估五月茶对 P-gp 活性的调节作用，研究了在不存在或存在 MI 或 MT70 的情况下，Caco-2 细胞摄取 fexofenadine（FEX）的情况。通过在雄性 Wistar 大鼠中与每个提取物共同给予咪达唑仑（MDZ），评估 CYP3A 活性的影响。测定药物的药代动力学参数，并与对照组进行比较。MT70 提取物中总酚类、单宁和类黄酮的含量约为 MI 提取物的两倍。

结果

在提取物存在的情况下，Caco-2 细胞摄取 P-gp 标记物（FEX）的量从对照（1.7 ± 0.4 ng·mg-1 蛋白）分别增加到 MI（3.5 ± 0.2 ng·mg-1 蛋白）和 MT70（4.4 ± 0.5 ng·mg-1 蛋白）。当与 MDZ（CYP3A 底物）口服共同给予时，提取物增加了药物的 AUC（0-∞）（对照：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）和 Cmax（对照：407.7 ± 90.4 ng·mL-1；MI：1770.5 ± 764.5 ng·mL-1；MT70：1987.2 ± 544.9 ng·mL-1），表明药物的口服清除率降低了 50%。当咪达唑仑静脉给予时，未观察到这种作用。