Effect of quercetin on the pharmacokinetics of selexipag and its active metabolite in beagles

• Published in: Pharmaceutical biology 2022-12, Vol.60 (1), p.1-8
• Main Authors: Luo, Shun-bin, Gu, Er-min, Chen, Yu-ao, Zhou, Shi-chen, Fan, Chen, Xu, Ren-ai
• Format: Article
• Language: English
• Subjects: Acetamides - pharmacokinetics; Acetates - pharmacokinetics; ACT-333679; Animals; Antihypertensive Agents - pharmacokinetics; Area Under Curve; Chromatography, High Pressure Liquid; CYP2C8; Cytochrome P-450 CYP2C8 Inhibitors - pharmacology; Cytochrome P450; Dogs; Drug interaction; Female; Flavonoids; Glycosides; Herb-Drug Interactions; inhibit; Liquid chromatography; Male; Mass spectroscopy; metabolism; Oral administration; Pharmacokinetics; Pyrazines - pharmacokinetics; Quercetin; Quercetin - pharmacology; Tandem Mass Spectrometry; UPLC-MS/MS
• ISSN: 1388-0209; 1744-5116
• DOI: 10.1080/13880209.2021.2005636

As an inhibitor cytochrome P450 family 2 subfamily C polypeptide 8 (CYP2C8), quercetin is a naturally occurring flavonoid with its glycosides consumed at least 100 mg per day in food. However, it is still unknown whether quercetin and selexipag interact. The study investigated the effect of quercetin on the pharmacokinetics of selexipag and ACT-333679 in beagles. The ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used to investigate the pharmacokinetics of orally administered selexipag (2 mg/kg) with and without quercetin (2 mg/kg/day for 7 days) pre-treatment in beagles. The effect of quercetin on the pharmacokinetics of selexipag and its potential mechanism was studied through the pharmacokinetic parameters. The assay method was validated for selexipag and ACT-333679, and the lower limit of quantification for both was 1 ng/mL. The recovery and the matrix effect of selexipag were 84.5-91.58% and 94.98-99.67%, while for ACT-333679 were 81.21-93.90% and 93.17-99.23%. The UPLC-MS/MS method was sensitive, accurate and precise, and had been applied to the herb-drug interaction study of quercetin with selexipag and ACT-333679. Treatment with quercetin led to an increased in C max and AUC 0-t of selexipag by about 43.08% and 26.92%, respectively. While the ACT-333679 was about 11.11% and 18.87%, respectively. The study indicated that quercetin could inhibit the metabolism of selexipag and ACT-333679 when co-administration. Therefore, the clinical dose of selexipag should be used with caution when co-administered with foods high in quercetin.