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首页> 外文期刊>Journal of Pharmacy and Pharmacology >Effects of myricetin, an antioxidant, on the pharmacokinetics of losartan and its active metabolite, EXP-3174, in rats: possible role of cytochrome P450 3A4, cytochrome P450 2C9 and P-glycoprotein inhibition by myricetin.
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Effects of myricetin, an antioxidant, on the pharmacokinetics of losartan and its active metabolite, EXP-3174, in rats: possible role of cytochrome P450 3A4, cytochrome P450 2C9 and P-glycoprotein inhibition by myricetin.

机译：抗氧化剂杨梅素对氯沙坦及其活性代谢物EXP-3174在大鼠体内的药代动力学的影响：杨梅素对细胞色素P450 3A4，细胞色素P450 2C9和P糖蛋白抑制的可能作用。

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OBJECTIVES: The effects of myricetin, a natural flavonoid, on the pharmacokinetics of losartan and its active metabolite, EXP-3174, were investigated in rats. Losartan and myricetin interact with cytochrome P450 (CYP) enzymes and P-glycoprotein, and the increase in the use of health supplements may result in myricetin being taken concomitantly with losartan as a combination therapy to treat or prevent cardiovascular diseases. METHODS: The pharmacokinetic parameters of losartan and EXP-3174 were determined after oral administration of losartan (9 mg/kg) to rats in the presence or absence of myricetin (0.4, 2 and 8 mg/kg). The effects of myricetin on P-glycoprotein as well as CYP3A4 and CYP2C9 activity were also evaluated. KEY FINDINGS: Myricetin inhibited CYP3A4 and CYP2C9 enzyme activity with a 50% inhibition concentration of 7.8 and 13.5 microm, respectively. In addition, myricetin significantly enhanced the cellular accumulation of rhodamine 123 in MCF-7/ADR cells overexpressing P-glycoprotein in a concentration-dependent manner. The pharmacokinetic parameters of losartan were significantly altered by myricetin compared with the control. The presence of myricetin (2 or 8 mg/kg) increased the area under the plasma concentration-time curve of losartan by 31.4-61.1% and peak plasma concentration of losartan by 31.8-50.2%. Consequently, the absolute bioavailability of losartan in the presence of myricetin increased significantly (P < 0.05, 2 mg/kg; P < 0.01, 8 mg/kg) compared with the control. There was no significant change in the time to reach the peak plasma concentration, apparent volume of distribution at steady state or terminal half-life of losartan in the presence of myricetin. Furthermore, concurrent use of myricetin (8 mg/kg) significantly decreased the metabolite-parent area under the plasma concentration-time curve ratio by 20%, implying that myricetin may inhibit the CYP-mediated metabolism of losartan to its active metabolite, EXP-3174. CONCLUSIONS: The enhanced bioavailability of losartan may be mainly due to inhibition of the CYP3A4- and CYP2C9-mediated metabolism of losartan in the small intestine or in the liver, and the P-glycoprotein efflux pump in the small intestine by myricetin.
机译：目的：在大鼠中研究了一种天然类黄酮杨梅素对氯沙坦及其活性代谢物EXP-3174的药代动力学的影响。氯沙坦和杨梅素与细胞色素P450（CYP）酶和P-糖蛋白相互作用，健康补充剂的使用增加可能导致杨梅素与氯沙坦同时服用，作为治疗或预防心血管疾病的联合疗法。方法：在存在或不存在杨梅素（0.4、2和8 mg / kg）的情况下，对大鼠口服洛沙坦（9 mg / kg），测定氯沙坦和EXP-3174的药代动力学参数。还评估了杨梅素对P-糖蛋白以及CYP3A4和CYP2C9活性的影响。主要发现：杨梅素抑制CYP3A4和CYP2C9酶的活性，其50％抑制浓度分别为7.8和13.5微米。此外，杨梅素以浓度依赖性方式显着增强了过表达P-糖蛋白的MCF-7 / ADR细胞中若丹明123的细胞蓄积。与对照相比，杨梅素显着改变了氯沙坦的药代动力学参数。杨梅素（2或8 mg / kg）的存在使氯沙坦的血浆浓度-时间曲线下面积增加了31.4-61.1％，氯沙坦的峰值血浆浓度增加了31.8-50.2％。因此，与对照相比，在存在杨梅素的情况下，氯沙坦的绝对生物利用度显着增加（P <0.05，2 mg / kg; P <0.01，8 mg / kg）。在存在杨梅素的情况下，达到峰值血浆浓度的时间，稳态下的表观分布体积或氯沙坦的终末半衰期没有明显变化。此外，同时使用杨梅素（8 mg / kg）可使血浆浓度-时间曲线比率下的代谢物-母体面积显着降低20％，这表明杨梅素可能会抑制CYP介导的氯沙坦代谢为其活性代谢物EXP-。 3174。结论：氯沙坦生物利用度的提高可能是由于抑制了小肠或肝脏中CYP3A4-和CYP2C9介导的氯沙坦代谢以及小肠中P-糖蛋白外排泵的作用。

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