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. 2022 Dec;60(1):1-8.
doi: 10.1080/13880209.2021.2005636.

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

Shun-Bin Luo  1 , Er-Min Gu  2 , Yu-Ao Chen  3 , Shi-Chen Zhou  3 , Chen Fan  3 , Ren-Ai Xu  4
Affiliations

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

Shun-Bin Luo et al. Pharm Biol. 2022 Dec.

Abstract

Context: 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.

Objective: The study investigated the effect of quercetin on the pharmacokinetics of selexipag and ACT-333679 in beagles.

Materials and methods: 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.

Results: 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 Cmax and AUC0-t of selexipag by about 43.08% and 26.92%, respectively. While the ACT-333679 was about 11.11% and 18.87%, respectively.

Discussion and conclusion: 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.

Keywords: ACT-333679; CYP2C8; UPLC-MS/MS; inhibit; metabolism.

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Conflict of interest statement

The authors in this manuscript declare no potential conflicts of interest.

Figures

Figure 1.
Figure 1.
The chemical structure of selexipag (A), its active metabolite ACT-333679 (B), and quercetin (C).
Figure 2.
Figure 2.
The product-ion mass spectrum of the analytes in the present study: (A) Selexipag; (B) ACT-333679; (C) Marimastat (IS).
Figure 3.
Figure 3.
The representative chromatograms of the analytes in the present study: (A) a blank plasma sample; (B) a blank plasma sample spiked with selexipag, ACT-333679, and Marimastat (IS); (C) a beagle plasma sample after oral administration of selexipag.
Figure 4.
Figure 4.
Mean plasma concentration-time profiles of selexipag (A) and ACT-333679 (B) in beagle dogs after orally administered selexipag (2 mg/kg) with and without quercetin pre-treatment (n = 6, Mean ± SD).
Figure 5.
Figure 5.
The semi-log transformed mean plasma concentration-time profiles of selexipag (A) and ACT-333679 (B) in beagle dogs after orally administered selexipag (2 mg/kg) with and without quercetin pre-treatment (n = 6, Mean ± SD).
See this image and copyright information in PMC

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