Department of Pharmacology, College of Pharmacy, Dali University, Dali, China.
Department of Cardiology, The First Affiliated Hospital, Dali University, Dali, China.
Xenobiotica. 2021 May;51(5):616-623. doi: 10.1080/00498254.2021.1880670. Epub 2021 Feb 3.
1. Breviscapine was an active ingredient of flavonoid glycosides. Our present study was conducted to evaluate the impact of breviscapine on the pharmacokinetics of losartan and its active metabolite E-3174, and that relationship with the gene polymorphism of CYP2C9 in healthy Chinese volunteers, to provide a basis for clinical rational drug use.2. The genotypes of 217 healthy Chinese subjects were determined using PCR-RFLP. Twelve healthy subjects were selected and were known CYP2C9 genotypes (six CYP2C9*1/3 and six CYP2C91/1) in a two-phase randomised crossover design study. These subjects were given daily doses of 120 mg (40 mg, three times a day) of breviscapine or a placebo for 14 days, followed by 50 mg losartan on day 15.3. Compared with individuals carrying the CYP2C91/1 genotype, the CYP2C91/3 genotype showed an increase in the AUC (833.6 ± 379.8 ng h ml vs. 526.1 ± 140.1 ng h ml, < 0.05) and a decrease in the MR (the metabolic ratio of losartan, AUC/AUC) (2.67 ± 1.40 vs. 4.56 ± 0.83, < 0.05) of losartan during the placebo treatment phase. Individuals with genotype CYP2C91/3 showed a significant increase in AUC (2335 ± 851.8 ng h ml vs. 1927 ± 949.5 ng h ml, < 0.05) and AUC (2363 ± 875.6 ng h ml vs. 1966 ± 966.1 ng h ml, < 0.05) of E-3174 after breviscapine treatment compared to the placebo group.4. In healthy subjects, breviscapine had no significant effect on the pharmacokinetics of losartan. The activity of CYP2C9 enzyme to losartan metabolism was more significant in subjects with CYP2C91/3 than those with CYP2C91/*1 genotype.
灯盏花乙素是黄酮类化合物的一种活性成分。本研究旨在评价灯盏花乙素对健康中国志愿者体内洛沙坦及其活性代谢物 E-3174 药代动力学的影响及其与 CYP2C9 基因多态性的关系，为临床合理用药提供依据。
采用 PCR-RFLP 法对 217 例健康中国受试者的基因型进行检测。采用二阶段随机交叉设计，选择 12 例已知 CYP2C9 基因型（6 例 CYP2C9*1/3 和 6 例 CYP2C91/*1）的健康受试者，每天给予 120mg（40mg，每日 3 次）灯盏花乙素或安慰剂 14 天，然后在第 15 天给予 50mg 洛沙坦。
与 CYP2C9*1/1 基因型个体相比，CYP2C91/3 基因型个体洛沙坦的 AUC（833.6±379.8ng·h·ml-1 比 526.1±140.1ng·h·ml-1，<0.05）增加，MR（洛沙坦的代谢比，AUC/AUC）（2.67±1.40 比 4.56±0.83，<0.05）降低，在安慰剂治疗阶段。CYP2C91/*3 基因型个体的 AUC（2335±851.8ng·h·ml-1 比 1927±949.5ng·h·ml-1，<0.05）和 AUC（2363±875.6ng·h·ml-1 比 1966±966.1ng·h·ml-1，<0.05）均显著增加。
在健康受试者中，灯盏花乙素对洛沙坦的药代动力学无显著影响。CYP2C9*1/3 基因型受试者洛沙坦代谢中 CYP2C9 酶的活性明显高于 CYP2C91/*1 基因型受试者。
