Inhibition of total flavonoids from <i>Abelmoschus Manihot</i> on cytochrome P450

XU Yao; PENG Ying; WANG Guangji; SUN Jianguo

doi:10.11665/j.issn.1000-5048.2023021402

Journal of China Pharmaceutical University > 2023 > 54(2): 208-217. > DOI: 10.11665/j.issn.1000-5048.2023021402

XU Yao, PENG Ying, WANG Guangji, SUN Jianguo. Inhibition of total flavonoids from Abelmoschus Manihot on cytochrome P450[J]. Journal of China Pharmaceutical University, 2023, 54(2): 208-217. DOI: 10.11665/j.issn.1000-5048.2023021402

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Inhibition of total flavonoids from Abelmoschus Manihot on cytochrome P450

Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China

Funds: This study was supported by the Innovation Fund for Medical Sciences of Chinese Academy of Medical Sciences (No.2021-I2M-5-011)

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Received Date: February 13, 2023
Revised Date: April 07, 2023

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Abstract

Abstract

To investigate the influential mechanism of total flavonoids from Abelmoschus Manihot (HKZ) on cytochrome P450 (CYP450) isoforms in human liver microsomes and to verify its effect on the most significantly inhibited subtype CYP2C9 in rats.The inhibitory effects of HKZ on human CYP3A4, CYP2C9, CYP2C19, CYP2E1, CYP1A2 and CYP2D6 were evaluated through the cocktail method using ultra-performance liquid chromatography tandem mass spectrometry, then its inhibitory mechanism was investigated and kinetic parameters of enzyme inhibition were calculated By comparing the pharmacokinetic behaviors of tolbutamide after single or multiple administration of 200 mg/kg HKZ and equal dose of CMC-Na in rats, the effects of HKZ on CYP2C11 enzyme (CYP2C9 isoenzyme) was estimated.The results indicated the significant inhibitory effect of HKZ on CYP2C9 and CYP2E1 with IC₅₀ of 3.22 and 8.64 μg/mL, respectively. Also, it showed certain inhibitory ability on other isoforms with IC₅₀ of 20-30 μg/mL.As demonstrated, HKZ may not be a time-dependent inhibitor which competitively inhibited CYP2E1 and CYP2C9 with K_i of 3.84 and 6.33 μg/mL.In contrast, it showed noncompetitive inhibition on CYP3A4 mediated testosterone-6β-hydroxylation and midazolam-4-hydroxylation reaction with K_i of 7.37 and 3.32 μg/mL.It was also a noncompetitive inhibitor of CYP1A2, CYP2D6 and CYPC219 with K_i values of 8.66, 11.49 and 21.94 μg/mL. HKZ did not change the pharmacokinetic parameters of CYP2C11 probe substrate tolbutamide in rat, but it affected the AUC_0-t, c_max of 4-hydroxytolubutamide (P < 0.05). Therefore, drug-drug interaction mediated by CYP450 should be considered in clinical study.
- total flavonoids from Abelmoschus Manihot,
- CYP450 enzyme,
- inhibition kinetics,
- pharmacokinetics,
- tolbutamide

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