Study on the effect of the components of salviae miltiorrhizae on the metabolism of fluvastatin and its mechanism based on the polymorphism of cytochrome P450 2C9
10.13699/j.cnki.1001-6821.2017.21.022
- VernacularTitle:基于细胞色素P450 2C9的基因多态性研究丹参组分对氟伐他汀代谢影响及其机制
- Author:
Gui-Chen MA
1
;
Yi-Fei DUAN
;
Hong ZHANG
;
Gao-Feng JIN
;
Ming-Yi LIU
;
Yu-Qing XIONG
Author Information
1. 南昌大学临床药理研究所
- Keywords:
component of salviae miltiorrhizae;
fluvastatin;
cytochrome P450 2C9;
gene polymorphism;
metabolism
- From:
The Chinese Journal of Clinical Pharmacology
2017;33(21):2171-2174
- CountryChina
- Language:Chinese
-
Abstract:
Objective To identify the effect of six components of salviae miltiorrhizae on the metabolism of fluvastatin in the human liver microsomes (HLMs) and to further explore the effect of cryptotanshinone and dihydrotanshinone Ⅰ on the metabolism of fluvastatin based on the polymorphism (* 1,* 2,* 3) of cytochrome P450 2C9 (CYP2C9).Methods Establishing the incubation system of HLMs and recombinase and determining the concentration of fluvastatin by HPLC.To calculate the enzyme kinetic parameters,half maximal inhibitory concentration (IC50) and inhibition constant (Ki) so as to compare the impact of different CYP2C9 mutation site on the metabolism of fluvastatin and the influence of components of salviae miltiorrhizae on the metabolism process.Results It was shown that cryptotanshinone and dihydrotanshinone Ⅰ exerted significant inhibition on the metabolism of fluvastatin and the residual activity were 30.24％,14.52％ respectively when the concentrations were 10 μmol · L-1 in the HLMs.However,other exhibited no inhibitory effect.The michaelis constant (Km),maximum velocity (Vmax) and intrinsic clearance (CLint) of CYP2C9 * 1,* 2,* 3 recombinase-catalyzed fluvastatin was (1.56±0.21),(1.79±0.25),(2.32±0.43)μmol· L-1,(41.75±1.67),(26.55±1.08),(12.85±0.79) pmol · min-1 · mg-1 and 26.71,14.86,5.53 μL · min-1 · mg-1 respectively.It was indicated that the metabolic activity of CYP2C9 * 1 was stronger than * 2,* 3.The IC50 value of CYP2C9 * 1,* 2,* 3 recombinase-catalyzed fluvastatin by cryptotanshinone and dihydrotanshinone Ⅰ was (1.74 ± 0.41),(2.64 ± 0.81),(3.17 ± 0.32) μmol · L-1 and (0.19 ±0.09),(0.56 ±0.16),(1.52 ±0.34) μmol · L-1.The IC50 and Ki value of CYP2C9 * 1 was less than * 2 and * 3 but there was statistical significance between the * 1 and * 3 with respect to the difference of IC50 and Ki.Conclusion The mutation site of 430(C ＞ T) and 1075 (A ＞ C) could influence the metabolic activity of CYP2C9.The cryptotanshinone and dihydrotanshinone Ⅰ exerted strong inhibitory effect against CYP2C9 recombinase-catalyzed fluvastatin and their inhibitions on CYP2C9 * 1,* 2,* 3 recombinase-catalyzed fluvastatin were different.
