ABSTRACT
Objective::To evaluate the effects of Valeriana amurensis roots and rhizomes extract and its active constituents on the activities of six major cytochrome P450 (CYP450) enzymes in human liver microsomes. Method::Coumarin, bupropion, tolbutamide, omeprazole, dextromethorphan and testosterone were used as probe substrates for CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4, respectively. Taking their specific metabolites of hydroxylation or demethylation (7-hydroxycoumarin, hydroxybupropion, 4-hydroxytolbutamide, 5-hydroxyomeprazole, dextromethorphan, 6β-hydroxytestosterone) as indicators of enzyme activities. The analytical indexes were used to establish an in vitro model of human liver microsomes of Cocktail probe substrates. This method was applied to evaluate the effects of V. amurensis roots and rhizomes extract and its active constituents on human liver microsomal enzymes. Result::The V. amurensis roots and rhizomes extract had different inhibitory effects on CYP2B6, CYP2C9, CYP2D6 and CYP3A4, their half-inhibitory concentration (IC50) values were 87.49, 1.73, 68.29, 2.80 mg·L-1, respectively. Among the 9 lignans, (-)-massoniresinol-3α-O-β-D-glucopyranoside had a moderate inhibitory effect on CYP2A6 with an IC50 value of 8.51 μmol·L-1, 8, 8′-dihydroxypinoresinol-4, 4′-di-O-β-D-glucopyranoside had a moderate inhibitory effect on CYP2D6 with an IC50 value of 8.73 μmol·L-1, (+)-medioresinol-4, 4′-O-di-β-D-glucopyranoside had a moderate inhibitory effect on CYP2B6 and CYP2C9 with IC50 values of 5.41 μmol·L-1 and 8.20 μmol·L-1. Conclusion::The V. amurensis roots and rhizomes extract and its active constituents have inhibitory effects on liver CYP450 enzymes. Therefore, in the clinical study of new drugs, it is necessary to fully evaluate the risk of drug interactions caused by combination therapy.
ABSTRACT
Objective:To study on the effect of Inula cappa extract on the activities of six cytochrome P450(CYP450) enzymes in rats by Cocktail probe method. Method:Rats in the I. cappa high and low dose groups were given oral administration of active fractions of I. cappa at a dose of 8.127,2.709 g·kg-1·d-1 of the material for 7,14 d,repectively.Probe drugs(caffeine,midazolam,tolbutamide,omeprazole,metoprolol,chlorzoxazone) were simultaneously injected to rats after administration.Plasma was collected at different time after the administration of probe drugs.The plasma concentrations of these six probes were measured by UPLC-MS and their corresponding pharmacokinetic parameters were calculated with DAS 2.0. Result:Compared with the control group,only the apparent volume of distribution(V) of midazolam was increased;area under the curve(AUC0-t and AUC0-∞)and half-life period(T1/2) of caffeine,midazolam,tolbutamide and omeprazole were increased and the clearance rate(CL) of them was decreased in rats of I. cappa groups.But there were no differences in pharmacokinetic parameters of chlorzoxazone and metoprolol. Conclusion:I. cappa can reduce the enzymatic activities of CYP3A,CYP1A2,CYP2C9 and CYP2C19 in rats at different degree,among which CYP3A is the strongest.
ABSTRACT
This study was designed to explore the impact of depression on kidney-yang deficiency in rats. Rats were repeatedly injected with hydrocortisone for 21 days to establish the depression model with kidneyyang deficiency. Tolbutamide, chlorzoxazone, theophylline, midazolam, omeprazole and dextromethorphan were used as substrates of CYP2C6, CYP2E1, CYP1A2, CYP3A2, CYP2D1, and CYP2D2 to test the depression impact on drug metabolism. Plasma concentrations of six CYP450 were determined by LC-MS/MS and used as pharmacokinetic parameters. Consequently, metabolism of theophylline, chlorzoxazone and tolbutamide were accelerated significantly in the model relative to the control (P<0.01), but dextromethorphan, omeprazole and midazolam did not exhibit a significant difference. The present study suggests that depression with kidneyyang deficiency had a strong induction of CYP2E1 and moderate induction of CYP1A2, CYP2C6 in the rat model.