[Pharmacokinetic differences and related mechanisms of ginkgo flavone aglycone in normal and atherosclerotic rats in vivo]

This study aimed to compare the pharmacokinetics of ginkgo flavone aglycone(GA) in plasma after oral administration of GA in normal and atherosclerosis(AS) model rats and to explore the mechanism of pharmacokinetic differences. The AS rats were prepared by using high-fat diets. Rats in the normal and AS model groups were orally given 200 mg·kg~(-1) GA, blood samples were collected at different time points, plasma was separated, and the plasma concentrations of quercetin, kaempferol and isorhamnetin in the normal and AS model groups were determined by ultra-performance liquid chromatography-mass spectrometry(UPLC-MS/MS). The relevant pharmacokinetic parameters were calculated by WinNonlin 8.2 software. Western blot analysis was used to detect the expressions of CYP1A2, CYP3A4, CYP2C19 and CYP2C9 in liver tissue. Fluorescent quantitative real-time polymerase chain reaction(RT-PCR) was used to detect the expression of multiple drug resistance 1(MDR1) gene at mRNA level in intestinal villi. The T_(max) of quercetin, kaempferol and isorhamnetin in the AS model group was 2.00, 2.50(P<0.05) and 2.53 times that in the normal group, respectively, and the C_(max) was 46.98%, 77.09% and 57.19% of that in the normal group(P<0.01). The t_(1/2) of quercetin, kaempferol and isorha-mnetin in the model group was 1.76(P<0.05), 1.10 and 2.81(P<0.01) times those in the normal group, respectively. Compared with those in the normal group, the expressions of CYP1A2 and CYP2C19 in the liver of AS rats were decreased by 38% and 35%, respectively(P<0.05), and the expression of CYP3A4 was increased by 1.36 times(P<0.05), while the expression of CYP2C9 was not significantly different. The messenger RNA(mRNA) expression of MDR1 in intestinal villi of AS rats was increased by 1.7 times(P<0.05). In conclusion, the oral absorption of quercetin, kaempferol and isorhamnetin in AS rats was reduced, with slower absorption and metabolism rate in vivo, which might result from the high expression of P-glycoprotein(P-gp) in the small intestine and the altered expressions of CYP1A2, CYP3A4 and CYP2C19 in liver tissue.