Xing Liying, Liu Ya-Nan, Yao Hongye, Wang Tingting, Xie Fuchen, Luo Shunbin, Luo Pingping, Tang Shengling
The First People's Hospital of Jiashan, Jiaxing, China.
The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
Front Pharmacol. 2022 Jun 16;13:874973. doi: 10.3389/fphar.2022.874973. eCollection 2022.
Relugolix, a gonadotropin-releasing hormone (GnRH) receptor antagonist, has been well studied in the treatment of endometriosis symptomatic. It is mainly metabolized by the CYP3A subfamily of P450 enzymes, while minorly metabolized by CYP2C8. Daidzein in different dose groups exhibited a certain induction on the mRNA expression level of CYP3A4 and resulted in the potent induction of CYP3A4. However, it is still unknown whether daidzein and relugolix interact. We developed an effective ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method to study the effect of daidzein on the pharmacokinetics of relugolix in rats after oral administration of 12 mg/kg relugolix in a single or mixed of 50 mg/kg daidzein. The results showed that the method had respectable linearity ( > 0.999) on the scale of 0.7-1000 ng/mL. The intra-day precision was between 3.0% and 8.4% in this assay, and the inter-day was between 4.0% and 11.7%. The intra-day accuracy was from -4.3% to 6.1%, and the inter-day was 2.9% to 12.1%. Another three key indicators, including the stability, the recovery rate of extraction and the new technique's matrix effect, were perfectly in accord with the test verification rule in the biological medium by the United States Food and Drug Administration. Meanwhile, treatment with daidzein led to a decrease in C and AUC of relugolix by about 15.56% and 21.36%, respectively. Although there was no statistical difference in pharmacokinetic parameters, it reflected the induction trend of daidzein on relugolix metabolism for food-drug interaction. It would provide reference and improvement value for subsequent experiments.
Relugolix是一种促性腺激素释放激素（GnRH）受体拮抗剂，已在症状性子宫内膜异位症的治疗方面得到充分研究。它主要由细胞色素P450酶的CYP3A亚家族代谢，而少量由CYP2C8代谢。不同剂量组的大豆苷元对CYP3A4的mRNA表达水平有一定诱导作用，并导致CYP3A4的显著诱导。然而，大豆苷元和Relugolix是否相互作用仍不清楚。我们开发了一种有效的超高效液相色谱串联质谱（UPLC-MS/MS）方法，以研究在大鼠口服12mg/kg Relugolix单次给药或与50mg/kg大豆苷元混合给药后，大豆苷元对Relugolix药代动力学的影响。结果表明，该方法在0.7-1000ng/mL范围内具有良好的线性（>0.999）。该测定法的日内精密度在3.0%至8.4%之间，日间精密度在4.0%至11.7%之间。日内准确度为-4.3%至6.1%，日间准确度为2.9%至12.1%。另外三个关键指标，包括稳定性、提取回收率和新技术的基质效应，完全符合美国食品药品监督管理局生物介质中的测试验证规则。同时，大豆苷元处理使Relugolix的C和AUC分别降低了约15.56%和21.36%。虽然药代动力学参数没有统计学差异，但它反映了大豆苷元对Relugolix代谢的诱导趋势，用于食物-药物相互作用。这将为后续实验提供参考和改进价值。
