Jana Snehasis, Rastogi Himanshu
Drug Discovery Research and Development Division, Trivedi Science Research Laboratory Pvt Ltd, Bhopal, 462026, India.
Suresh Gyan Vihar University, Mahal, Jagatpura, Jaipur, 302025, India.
Eur J Drug Metab Pharmacokinet. 2017 Oct;42(5):781-791. doi: 10.1007/s13318-016-0393-7.
Melatonin is a popular dietary supplement and also considered as pharmaceutical product for sleep disorders. Caffeic acid and quercetin are widely distributed in leafy vegetables, fruits, tea extract, and both are used as natural antioxidant. There is an immense concern for health researchers to study the herb/food-drug interactions of melatonin. It is mainly metabolized by CYP1A2 in human so that herbs/foods containing cytochrome P450 (CYP) inhibitors can affect pharmacokinetics of melatonin. By considering pharmacokinetic aspects, the present study was undertaken to evaluate the effects of caffeic acid and quercetin on Caco-2 cells permeability, metabolism, CYP1A inhibition in vitro assay systems and a single dose pharmacokinetics of melatonin in vivo rats.
The effects of caffeic acid and quercetin on melatonin permeability were tested in Caco-2 cells. Metabolic stability and CYP1A activity were investigated in rat liver microsomes (RLMs) using probe substrates (melatonin/phenacetin in vitro). Melatonin and phenacetin were incubated in RLMs with or without caffeic acid and quercetin, and the IC values were determined. The pharmacokinetics of melatonin conducted in rats after a single dose (15 mg/kg) pre-treatment with caffeic acid, quercetin and caffeic acid plus quercetin followed by oral dose of melatonin at 5 mg/kg. Analysis of all samples was with LC-MS/MS.
Caffeic acid and quercetin did not alter Caco-2 permeability of melatonin in apical to basolateral direction and vice versa. Melatonin was metabolized in rat liver microsomes, which was inhibited by both caffeic acid and quercetin through CYP1A. The concomitant oral administration of melatonin along with 15 mg/kg of caffeic acid or quercetin or caffeic acid plus quercetin significantly (p < 0.05) increased the AUC of melatonin by 30.0, 66.7 and 114.0%, respectively. The apparent oral rat plasma clearance (CL/F) of melatonin also decreased significantly (p < 0.05) by 28.78, 47.87 and 50% in presence of caffeic acid, quercetin and caffeic acid plus quercetin, respectively.
These findings suggest that caffeic acid and quercetin improved oral exposure of melatonin via CYP1A inhibition pathway.
褪黑素是一种广受欢迎的膳食补充剂，也被视为治疗睡眠障碍的药品。咖啡酸和槲皮素广泛分布于叶菜类蔬菜、水果、茶提取物中，二者均用作天然抗氧化剂。健康研究人员极为关注褪黑素的草药/食物与药物相互作用。在人体内，褪黑素主要由细胞色素P450 1A2（CYP1A2）代谢，因此含有细胞色素P450（CYP）抑制剂的草药/食物会影响褪黑素的药代动力学。基于药代动力学方面的考虑，本研究旨在评估咖啡酸和槲皮素对Caco-2细胞通透性、代谢、体外CYP1A抑制测定系统以及褪黑素在大鼠体内单剂量药代动力学的影响。
在Caco-2细胞中测试咖啡酸和槲皮素对褪黑素通透性的影响。使用探针底物（体外褪黑素/非那西丁）在大鼠肝微粒体（RLMs）中研究代谢稳定性和CYP1A活性。将褪黑素和非那西丁在有或无咖啡酸和槲皮素的情况下于RLMs中孵育，并测定IC值。在大鼠经咖啡酸、槲皮素以及咖啡酸加槲皮素预处理单剂量（15毫克/千克）后，再口服5毫克/千克褪黑素，进行褪黑素的药代动力学研究。所有样品均采用液相色谱-串联质谱法进行分析。
咖啡酸和槲皮素不会改变褪黑素在Caco-2细胞从顶侧向基底侧的通透性，反之亦然。褪黑素在大鼠肝微粒体中代谢，咖啡酸和槲皮素均通过CYP1A抑制其代谢。褪黑素与15毫克/千克咖啡酸或槲皮素或咖啡酸加槲皮素同时口服给药，显著（p<0.05）使褪黑素的AUC分别增加30.0%、66.7%和114.0%。在存在咖啡酸、槲皮素和咖啡酸加槲皮素的情况下，褪黑素的表观口服大鼠血浆清除率（CL/F）也分别显著（p<0.05）降低28.78%、47.87%和50%。
这些发现表明，咖啡酸和槲皮素通过抑制CYP1A途径改善了褪黑素的口服暴露。
