Effect of Baicalein on the Pharmacokinetics of Cilostazol and Its Two Metabolites in Rat Plasma Using UPLC-MS/MS Method

Qinghua Weng; Chaojie Chen; Jianhua Xiong; Ya-Nan Liu; Xinxin Pan; Ju Cui; Jian-Ping Cai; Ren-Ai Xu

doi:10.3389/fphar.2022.888054

Effect of Baicalein on the Pharmacokinetics of Cilostazol and Its Two Metabolites in Rat Plasma Using UPLC-MS/MS Method

Front Pharmacol. 2022 Apr 27:13:888054. doi: 10.3389/fphar.2022.888054. eCollection 2022.

Authors

Qinghua Weng¹, Chaojie Chen², Jianhua Xiong¹, Ya-Nan Liu², Xinxin Pan³, Ju Cui⁴, Jian-Ping Cai^{2

4}, Ren-Ai Xu²

Affiliations

¹ The Third Affiliated Hospital of Shanghai University (Wenzhou People's Hospital), Wenzhou, China.
² The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
³ School of Pharmacy, Wenzhou Medical University, Wenzhou, China.
⁴ The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, China.

Abstract

This study aimed to explore the effect of baicalein on the pharmacokinetics of cilostazol (CLZ) and its two metabolites 3,4-dehydro cilostazol (3,4-CLZ) and 4'-trans-hydroxy cilostazol (4'-CLZ) in rats using a newly established ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method. Ticagrelor was used as an internal standard (IS), then cilostazol and its two metabolites were separated by means of a UPLC BEH C18 column (2.1 mm × 50 mm, 1.7 μm) using gradient elution method with 0.4 ml/min of flow rate. Acetonitrile as organic phase and water with 0.1% formic acid as aqueous phase constructed the mobile phase. Selective reaction monitoring (SRM) mode and positive ion mode were preferentially chosen to detect the analytes. Twelve SD rats were divided into two groups (n = 6) when CLZ was administered orally (10 mg/kg) with or without oral baicalein (80 mg/kg). The selectivity, linearity, recovery, accuracy, precision, matrix effect and stability of UPLC-MS/MS assay were satisfied with the standards of United States Food and Drug Administration guidelines. In control group, AUC_0-∞ and C_max of CLZ were 2,169.5 ± 363.1 ng/ml^*h and 258.9 ± 82.6 ng/ml, respectively. The corresponding results were 3,767.6 ± 1,049.8 ng/ml^*h and 308.6 ± 87.9 ng/ml for 3, 4-CLZ, 728.8 ± 189.9 ng/ml^*h and 100.3 ± 51.3 ng/ml for 4'-CLZ, respectively. After combination with baicalein, AUC_0-∞ and C_max of CLZ were 1.48, 1.38 times higher than the controls. Additionally, AUC_0-∞ and C_max were separately decreased by 36.12 and 19.54% for 3,4-CLZ, 13.11 and 44.37% for 4'-CLZ. Baicalein obviously alters the pharmacokinetic parameters of CLZ, 3,4-CLZ and 4'-CLZ in rats. These results suggested that there was a potential drug-drug interaction between baicalein and CLZ. Therefore, it must raise the awareness when concomitant use of CLZ with baicalein, the dosage regimen of CLZ should be taken into consideration, if this result is confirmed in clinical studies.

Keywords: 3, 4-dehydro cilostazol; 4′-trans-hydroxy cilostazol; UPLC-MS/MS; baicalein; cilostazol; pharmacokinetics.