College of Medicine, Chosun University, Gwangju, Republic of Korea.
J Pharm Pharmacol. 2010 Jul;62(7):908-14. doi: 10.1211/jpp.62.07.0012.
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.
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.
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.
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.
研究天然黄酮类化合物杨梅素对洛沙坦及其活性代谢物 EXP-3174 的药代动力学的影响。洛沙坦和杨梅素与细胞色素 P450（CYP）酶和 P-糖蛋白相互作用，而保健品的使用增加可能导致同时服用洛沙坦和杨梅素作为联合疗法来治疗或预防心血管疾病。
在存在或不存在杨梅素（0.4、2 和 8mg/kg）的情况下，口服给予洛沙坦（9mg/kg）后，测定洛沙坦和 EXP-3174 的药代动力学参数。还评价了杨梅素对 P-糖蛋白以及 CYP3A4 和 CYP2C9 活性的影响。
杨梅素对 CYP3A4 和 CYP2C9 酶活性的 50%抑制浓度分别为 7.8 和 13.5µM。此外，杨梅素以浓度依赖性方式显著增强 MCF-7/ADR 细胞中 P-糖蛋白过表达的罗丹明 123 的细胞积累。与对照相比，杨梅素显著改变了洛沙坦的药代动力学参数。存在杨梅素（2 或 8mg/kg）使洛沙坦的血浆浓度-时间曲线下面积增加 31.4-61.1%，使洛沙坦的峰血浆浓度增加 31.8-50.2%。因此，与对照相比，杨梅素存在时洛沙坦的绝对生物利用度显著增加（P<0.05，2mg/kg；P<0.01，8mg/kg）。在存在杨梅素的情况下，洛沙坦的达峰时间、稳态表观分布容积或终末半衰期没有显著变化。此外，同时使用杨梅素（8mg/kg）使代谢物-母体的血浆浓度-时间曲线下面积比降低 20%，表明杨梅素可能抑制洛沙坦向其活性代谢物 EXP-3174 的 CYP 介导的代谢。
洛沙坦生物利用度的提高可能主要归因于杨梅素抑制小肠或肝脏中的 CYP3A4 和 CYP2C9 介导的洛沙坦代谢，以及小肠中的 P-糖蛋白外排泵。
