Oxymatrine induce CYP2D6 and CYP3A4 in rats: a randomized, blinded study based on the HPLC-MS and cocktail method

Background The effect of oxymatrine (OMT) on cytochrome P450 (CYP) enzymes has been understudied. METHODS: This study was a blinded, randomized experiment. OMT and control groups were established. Sprague-Dawley rats were administrated oxymatrine 100 mg/kg or the same volume of saline by gavage daily, respectively. 7 days later, Cocktail probe solution was injected via tail vein according to body weight. Omeprazole (CYP2C19 substrate), dextromethorphan (CYP2D6 substrate) and midazolam (CYP3A4 substrate) were selected as probes for the cocktail method. A modified High-performance liquidchromatography/tandem mass spectrometry (HPLC-MS) method was used to determine the concentrations at multiple time points after administration of the probes, and then the changes in pharmacokinetic (PK) parameters were compared between the two groups. Results The area under the concentration-time curve (AUC) and peak concentration (C _max ) of CYP3A4 substrate midazolam and CYP2D6 substrate dextromethorphan were significantly lower and end elimination clearance (Cl _z ) was significantly higher in the OMT group compared with the control group. Moreover, the area under the moment curve (AUMC), end elimination half-life time (t _1/2z ) and volume of distribution calculated based on the end-elimination phase (V _z ) of dextromethorphan were also significantly decreased. However, no significant difference between groups was seen for the 2C19 substrate omeprazole. Conclusion OMT may induce CYP2D6 and CYP3A4 in rats, thus altering the PK parameters of substrate metabolism. The effects of OMT need to be investigated more further in the future for more CYP subtypes, and especially a cocktail study in humans is needed to verify the potential drug-drug interaction of OMT.