巴豆生物碱药动学研究及体内抗肺癌作用初步评价

Pharmacokinetics studies and preliminary evaluation on anti-lung cancer of Croton alkaloids in vivo

目的肺癌是常见的恶性肿瘤,巴豆生物碱(crolon alkaloid,CA)具有抑制肺癌细胞生长并促进其凋亡的作用。本研究旨在评价CA注射给药后的药动学及抗肺癌的药效学。方法以CA为原料,制成CA注射剂;SD大鼠为模型,考察1.2mg/kg剂量单次注射后巴豆苷和木兰花碱的药时曲线、总体暴露量、半衰期等相关药动学参数。将48只荷瘤裸鼠随机分成模型组、阳性对照组和巴豆生物碱组,每组16只,皮下接种A549(人源肺癌)细胞建立异位肺癌裸鼠模型。CA组荷瘤裸鼠以1.2mg/kg剂量(以CA剂)连续注射7d,考察肿瘤生长曲线、肿瘤质量、体质量、肝脾指数及生存时间等指标,并采用SPSS 16.0进行统计学分析。结果大鼠血浆中巴豆苷和木兰花碱在1~500ng/mL范围内具有较好的线性关系,巴豆苷的线性方程为y=0.025 1x+0.134(r=0.998 7),木兰花碱的线性方程为y=0.003 8x+0.027(r=0.999 5),且它们的提取回收率、稳定性及测定的精密度和准确度均符合生物样品测定要求。CA经单次注射后,巴豆苷的总体暴露量(AUC0-∞)为(157.2±43.1)μg·h/L、半衰期(t1/2)为(3.9±0.6)h;木兰花碱的总体暴露量(AUC0-∞)为(23.9±7.2)μg·h/L,半衰期(t1/2)为(4.3±1.8)h。经CA治疗7d后,荷瘤裸鼠的肿瘤生长被明显抑制(F=12.55,P=0.036),抑瘤率为53.62%;平均生存时间明显延长(F=37.62,P<0.001),平均生存时间为30d;且体质量、肝指数及脾指数均未出现明显异常(F值分别为2.01、2.98、4.23,均P>0.05)。结论 CA具有较好的体内暴露量(area under the concentration versus time curve,AUC),能够显著抑制肺癌的生长,实现肺癌的治疗。

OBJECTIVE Lung cancer is a common malignancy.Croton alkaloid（CA）can inhibit the growth of lung cancer cells and promote its apoptosis.This study is to evaluate the pharmacokinetics and pharmacodynamics of Croton alkaloids injections on anti-lung cancer.METHODS With Croton alkaloids as raw material,Croton alkaloids injections were prepared.Taking the SD rats as the model,the related pharmacokinetic parameters,such as the concentration-time curve,AUC,and t1/2,were investigated after Croton alkaloids were injected by 1.2 mg/kg dose.Forty-eight nude mice were randomly divided into three groups：model group,positive control group and Croton alkaloids group,each group was 16.The ectopic lung tumor-bearing nude mice model was established by subcutaneous inoculation of A549（human lung cancer）cells.The tumor-bearing mice of the Croton alkaloids group were given a continuous injection dose of 1.2 mg/kg（with croton alkaloid）for 7 days to evaluate their anti-tumor effect,tumor weight,body weight,liver index,spleen index and the survival time.SPSS16.0 was used for statistical analysis.RESULTS Crotonosine and magnesia had good linear relationship when their concentration was in the range of 1～500 ng/mL,and the linear equation of crotonoside was y=0.025 1 x＋0.134（r=0.998 7）,the linear equation of magnesia was y=0.003 8 x＋0.027（r=0.999 5）.Moreover,their extraction recovery,stability,precision and accuracy are all in line with the biological sample determination requirements.After single injection of Croton alkaloids,the AUC0-∞ value of crotonoside was（157.2±43.1）μg·h/L and its t1/2 value was（3.9±0.6）h.The AUC0-∞ value of magnoflorine was（23.9±7.2）μg·h/L and its t1/2 value was（4.3±1.8）h.After 7 days of treatment with Croton alkaloids,tumor growth of the tumor-bearing mice was significantly inhibited（F=12.55,P=0.036）,and the tumor inhibition rate was 53.62%.Their average survival time was significantly prolonged（F=37.62,P〈0.001）,and their average survival time was 30 days.Their body weight,liver index and spleen index had no obvious abnormalities（F=2.01,2.98,4.23,all P〈0.05）.CONCLUSION Croton alkaloids have good AUC,can significantly inhibit the growth of lung cancer,and ultimately achieve the treatment of lung cancer.