AUTHOR=Xing Liying , Liu Ya-nan , Yao Hongye , Wang Tingting , Xie Fuchen , Luo Shunbin , Luo Pingping , Tang Shengling 

TITLE=An Efficient UPLC-MS/MS Method Established to Detect Relugolix Concentration in Rat Plasma

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 13 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.874973

DOI=10.3389/fphar.2022.874973

ISSN=1663-9812

ABSTRACT=ABSTRACT 
Relugolix is a gonadotropin-releasing hormone (GnRH) receptor antagonist. It is metabolized mainly by the CYP3A subfamily of P450 enzymes with a smaller contribution by CYP2C8, and it has been well studied in the treatment of endometriosis symptomatic. 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 aneffective ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method to study the effect of daidzein on the pharmacokinetics of relugolix 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 (r2 > 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%. Three key indicators that including the stability, the recovery rate of extraction and the  matrix effect, which fitted the test verification rule in the biological medium that put forward by the US Food and Drug Administration. Meanwhile, treatment with daidzein led to a decrease in Cmax and AUC0–t 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 to relugolix for food-drug interaction. It would provide reference and improvement value for subsequent experiments.