The Potential Hepatotoxicity And Drug-Drug Interaction Of Xian-Ling-Gu-Bao Capsule

Objective:To study the potential hepatotoxicity of Xian-Ling-Gu-Bao capsule?XLGB?and the hepatotoxicity in combination with omeprazole and flutamide.Methods:1.C57 mice in half genders were randomly divided into four groups?n=12 per group?:vehicle control group,psoralea group?Content of Psoralea in Clinical Dosage of XLGB,9.25 mg/kg?,XLGB low-dose?Equivalent to clinical dose,308 mg/kg?and high-dose group?Equivalent to 8 times clinical dose,2464 mg/kg?.Mice were intragastric administered with XLGB or psoralea twice a day for six months.2.C57 mice in half genders were randomly divided into five groups?n=6 per group?:omeprazole group?OME,Equivalent to clinical dose,8.22 mg/kg?,The arrangement and administration scheme of that other groups are the same as method 1,XLGB and psoralea were intragastric administered twice a day for six months.OME was injected intraperitoneally to the mice at the fourth month when treatment with XLGB or psoralea,and administrated once a day for 3 months.3.Male C57 mice were randomly divided into two experiments:One was a short-term combination of high-dose XLGB and flutamide?FLU?,It was divided into vehicle control group,FLU group?300 mg/kg?,XLGB group?3080 mg/kg?,and XLGB+FLU group,n=3-4 per group.XLGB was intragastrically administered twice a day.FLU was intragastrically administered once a day for 4 days at the 6^th day of XLGB treatment.The other was a long-term combination of clinical dose XLGB and FLU.It was divided into vehicle control group,FLU group?150 mg/kg?,XLGB group?308 mg/kg?,and XLGB+FLU group,n=3-4 per group,XLGB was intragastrically administered twice a day while FLU was intragastrically administered once a day for 40 days.4.During the administration,mice tail vein blood samples were regularly collected.The blood and liver samples in each group were collected 12 h after the last treatment.the hepatotoxicity was evaluated by the Serum ALT,AST,ALP,LDH activities and the liver histopathology changes.The effects on hepatic P450 mRNA expression were measured by RT-PCR.Results:1.Compared with the vehicle control group,the serum ALP activities was increased in low-dose XLGB group.XLGB treatment induced inflammatory cell infiltrations in mice.Furthermore,XLGB increased the expression of hepatic Cyp1a2 and Cyp2c37 mRNA in male mice.2.Inflammatory cell infiltration was observed in XLGB+OME group mice,The degree of injury was the same as that of the group treated alone.XLGB+OME increased the expressions of the hepatic Cyp1a2 and Cyp2c37 mRNA in male mice.OME caused slight hepatocyte edema.The serum ALT levels were elevated and Slight inflammatory cell infiltration was observed in Psoralea+OME group.3.After short-term combined application of FLU and XLGB in high dosage,increase of liver coefficient and serum LDH levels was observed in XLGB+FLU group.Pathology study reveals that slight edema was observed in mice treatment with FLU alone,however,central venous dilation,blood sinus stenosis,swelling,massive cytoplasmic vacuoles and red lipid droplets were found in the liver tissue of XLGB+FLU group mice by H&E and oil red staining.XLGB+FLU elevated the expressions of hepatic Cyp1a2 mRNA.After long-term combined application of FLU and XLGB in clinical dosage,increase of liver coefficient and elevations of serum LDH activities were observed in XLGB plus FLU treated mice.Pathology study indicates that slight edema was observed in mice treatment with FLU alone,however,obvious swelling,focal necrosis and karyopycnosis were found in the liver tissue of XLGB+FLU group mice.Conclusion:After continuous administration for six months,XLGB causes chronic inflammations characterized by inflammatory cell infiltration in the liver of mice.The combined use of XLGB and OME does not increase the hepatotoxicity when compared with the single drug.The combined use of XLGB and FLU increase the hepatotoxicity when compared with the single drug.It may be related to the increase toxic metabolites of FLU induced by XLGB.