Study On The Effects Of Biqi Capsulae Prescription Compatibility On The Activities Of Cytochrome P450

Biqi capsulae is a new drug made and refined according to morden pharmaceutical preparation theory. It is for the treatment of rheumatic arthritis, rhermatoid arthritis, cervical spondylopathy, scapulohumeral periarthritis and so on. Biqi capsulae has the advantages of good and rapid healing efficacy and excellent pain relieveing effect. There is no report on the scientificalness and safety of prescription compatibility of Biqi capsulae. This study is an important part of Key Program of National Natural Science Foundation of China (No. 30630075). This study is aimed to investigate and evaluate the scientificalness and safety of Biqi capsulae prescription compatibility on cytochrome P450 (CYP450).A new high-throughput LC-MS/MS method was established to evaluate the in vivo activities of CYP1A2, 2C9, 2C19, 2D6 and 3A in rat plasma and urine. The five-specific probe substrates / metabolites include phenacetin / paracetamol (CYP1A2), tolbutamide / 4-hydroxytolbutamide / carboxytolbutamide (CYP2C9), mephenytoin / 4'-hydroxymephenytoin (CYP2C19), dextromethorphan / dextrorphan (CYP2D6) and midazolam / 1'-hydroxymidazolam (CYP3A). Using High-throughput Inhibitor Screening Kit, we determined the in vitro inhibitory effects of Biqi capsulae extract, active constituents of semen strychni (brucine and strychnine), brucine and strychnine combined with active constituents of Glycyrrhiza uralensis (glycyrrhetic acid and glycyrrhetinic acid) on the above 5 CYPs. Wistar rats were used to analyze and test the potential in vivo induction and (or) inhibition of constituents from Biqi prescription on the above 5 CYPs.A new"Cocktail"has been established, including probes of phenacetin, tolbutamide, mephenytoin, dextromephen and midazolam. A LC-MS/MS analytical method has been established to determine the above 5 probes and their corresponding metabolites. The results showed that brucine and strychnine had no in vitro inhibitory effect on 5 CYPs. It is possible that groups of brucine and strychnine combined with glycyrrhetic acid and glycyrrhetinic acid had in vitro inhibitory effects on CYP2C9 and CYP2C19. The in vivo results showed that Biqi capsulae prescription has compatibility on CYP450s. Compared with blank group, groups of"principal + assistant","principal + mediator","principal + assistant + complement","principal + assistant + mediator","principal + complement + mediator"and Biqi capsulae can significantly induce the activity of CYP1A2. Moreover, groups of"principal + assistant","principal + assistant + complement","principal + assistant + mediator"and Biqi capsulae can significantly induce the activity of CYP2C9.Biqi capsulae prescription has significant compatibility on CYP450s. These results provide important information and establish good foundation for further investigation on scientificalness and safety of Biqi capsulae prescription compatibility.