The Effect Of Doxorubicin-curcumin Compound Micelles On Metabolic Enzyme Activities

Cancer is the leading cause of death in the modern world.As an effective chemotherapeutic drug,doxorubicin is used clinically to treat various types of malignant tumors.It also increases the survival rate of cancer patients,and also exhibits a dose-dependent chronic toxicity and acute toxicity.Among them,cardiotoxicity and multidrug resistance of cancer are particularly prominent.Traditional Chinese medicine combined with chemotherapy for cancer has become an effective strategy to reduce the side effects of chemotherapy and fight against multidrug resistance of tumors.It has received extensive attention.The combination of chemotherapy drug doxorubicin and curcumin,a traditional Chinese medicine extract,can effectively alleviate toxic and side effects and antagonize cardiotoxicity.The drug system can reverse the problem of multidrug resistance of tumors,achieve passive targeting of drugs,and increase efficiency and reduce toxicity.At the same time,it increases the risk of drug-drug interactions,which may alter the efficacy of the drug and thus affect the effectiveness and safety of the drug.In this paper,doxorubicin-curcumin compound micelles were used as research objects to study the effects of single and multiple doses on the activity of drug-metabolizing enzymes in rat liver microsomes,in order to understand the pharmacokinetic characteristics and mechanism of compound preparations and guidance.An HPLC method for simultaneous determination of CYP1A2,CYP2E1,and CYP2C9 specific metabolite contents,and an HPLC method for determining CYP2D6 and CYP3A4 specific metabolite contents,respectively,were established.Single intraperitoneal injection of doxorubicin solution,curcumin micelles,doxorubicin solution and curcumin micelle mixed solution and doxorubicin-turmeric compound micelles,doxorubicin 20 mg/kg and turmeric The preparation of liver microsomes was prepared at 64 mg/kg,and the effects of the above-mentioned five CYP450 isoenzyme-specific metabolites on the CYP450 isoenzyme activity were evaluated by incubation in vitro.The results showed that doxorubicin-curcumin compound micelles had no effect on rat CYP450 isoenzyme activity after single administration.6 consecutive intravenous injections of doxorubicin solution,curcumin micelles,doxorubicin solution and curcumin micelle mixed solution and doxorubicin-turmeric compound micelles were administered as doxorubicin 1.75 mg/kg,respectively.After the preparation of liver microsomes with curcumin 5.6 mg/kg,the effects of the above-mentioned five CYP450 isoenzyme-specific metabolites on the CYP450 isoenzyme activity were evaluated by incubation in vitro.The results showed that the doxorubicin-curcumin compound micelles had no effect on the activities of CYP3A4,CYP2D6 and CYP2C9 in the untreated liver microsomes after multiple administrations,and induced the activities of CYP1A2 and CYP2E1.Single intraperitoneal injection of doxorubicin solution,curcumin micelles,doxorubicin solution and curcumin micelle mixed solution and doxorubicin-turmeric compound micelles,doxorubicin 20 mg/kg and turmeric After the preparation of liver microsomes at 64 mg/kg,the effect of the drug on the activity of UGTs was evaluated by the incubation rate of the specific substrate of UGTs.The results showed that the doxorubicin-curcumin compound micelle had no effect on the UGTs enzyme activity after a single administration.6 consecutive intravenous injections of doxorubicin solution,curcumin micelles,doxorubicin solution and curcumin micelle mixed solution and doxorubicin-turmeric compound micelles were administered as doxorubicin 1.75 mg/kg,respectively.After the preparation of liver microsomes with curcumin 5.6 mg/kg,the effect of repeated administrations on the activity of UGTs was evaluated by the incubation rate of UGTs specific substrate for the reduction of nitrophenol in vitro.The results showed that the doxorubicin-curcumin compound micelles induced the activity of UGTs.In summary,the doxorubicin-curcumin compound micelles have an effect on the activity of CYP1A2,CYP2E1,UGTs after repeated administration,and the drug interaction with the drugs metabolized by these two enzymes is relatively high.Pay attention when using it together.