安乃近水解产物4-甲氨基安替比林的毒理学研究
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摘要
目的通过开展安乃近水解产物4-甲氨基安替比林的毒理学试验,为安乃近原料药及其制剂的质量控制及临床用药安全提供实验依据。方法对4-甲氨基安替比林进行了急性毒性试验、亚急性毒性试验、小鼠骨髓微核试验、小鼠骨髓细胞染色体畸变试验及细胞毒性试验研究。结果 4-甲氨基安替比林LD50为509. 6 mg·kg~(-1),95%的可信限为471. 0～551. 4 mg·kg~(-1);亚急毒试验小鼠剖检主要脏器肉眼观察及组织病理学检查均无异常; 4-甲氨基安替比林250 mg·kg~(-1)以下剂量对小鼠无骨髓抑制作用,对小鼠骨髓细胞染色体无致畸变作用; 4-甲氨基安替比林0. 125 g·L~(-1)剂量组细胞毒性为4级。结论 4-甲氨基安替比林的急性全身毒性是安乃近的7. 0倍,细胞毒性较明显。提示安乃近制剂中5%的水解产物杂质限度要求对用药安全是否有影响还需进一步实验证明。
Objective To provide experimental basis for the quality control and clinical drug safety of analgin,the toxicologic study of 4-methylamine antipyrine,the hydrolysis product of analgin,was carried out in this study. Methods Acute systemic toxicity test,subacute systemic toxicity test,micronucleus test in mice,mice bone marrow chromosome aberration test and in vitro cytotoxicity test of 4-methylamine antipyrine were accomplished,respectively. Results The results indicated that LD50 of 4-methylamine antipyrine was 509. 6 mg·kg~(-1),95% confidence limit was 471. 0-551. 4 mg·kg~(-1); no abnormality was observed in subacute toxicity tests of mice by visual observing of autopsy major organs and histopathological examination. No bone marrowsuppression and chromosomal aberration were observed in mice below the dose of 250 mg·kg~(-1)dose of 4-methylamine antipyrine. And the M TT results showed that cytotoxic grade of4-methylamine antipyrine was 4 at the dose of 0. 125 g·L~(-1). Conclusions The toxicity of 4-methylamine antipyrine is 7. 0 times higher than analgin,and the cytotoxicity is obvious. And it suggests that further experiments is necessary to prove whether the impurity limit of 5% of hydrolysis product in the preparation of analgin has any effect on the safety of the drug.
Objective To provide experimental basis for the quality control and clinical drug safety of analgin,the toxicologic study of 4-methylamine antipyrine,the hydrolysis product of analgin,was carried out in this study. Methods Acute systemic toxicity test,subacute systemic toxicity test,micronucleus test in mice,mice bone marrow chromosome aberration test and in vitro cytotoxicity test of 4-methylamine antipyrine were accomplished,respectively. Results The results indicated that LD50 of 4-methylamine antipyrine was 509. 6 mg·kg~(-1),95% confidence limit was 471. 0-551. 4 mg·kg~(-1); no abnormality was observed in subacute toxicity tests of mice by visual observing of autopsy major organs and histopathological examination. No bone marrowsuppression and chromosomal aberration were observed in mice below the dose of 250 mg·kg~(-1)dose of 4-methylamine antipyrine. And the M TT results showed that cytotoxic grade of4-methylamine antipyrine was 4 at the dose of 0. 125 g·L~(-1). Conclusions The toxicity of 4-methylamine antipyrine is 7. 0 times higher than analgin,and the cytotoxicity is obvious. And it suggests that further experiments is necessary to prove whether the impurity limit of 5% of hydrolysis product in the preparation of analgin has any effect on the safety of the drug.
引文
[1]国家药典委员会.中华人民共和国药典:二部[M].北京:化学工业出版社,2005:211.
[2]国家药典委员会.中华人民共和国药典:二部[M].北京:中国医药科技出版社,2010:286.
[3]国家药典委员会.中华人民共和国药典:第一增补本[M].北京:中国医药科技出版社,2010:286-287,361-362.
[4]国家药典委员会.临床用药须知[M].北京:人民卫生出版社,2005:721-722.
[5]陈新谦,金有豫,汤光.新编药物学[M]. 17版.北京:人民卫生出版社,2011:200.
[6]谢先飞,曾繁典.安乃近不良反应及急性中毒事件的文献分析[J].药物流行病学杂志,2002,11(4):182-184.
[7] ARONSON J K. MEYLER药物副作用[M].北京:科学出版社,2007:2268-2269.
[8]雷光远,雷招宝.安乃近致死亡26例分析[J].医药导报,2012,31(11):1517-1521.
[9] HASSAN K,KHAZIM K,HASSAN F,et al. Acute kidney injury associated with metamizole sodium ingestion[J]. Renal Failure,2011,33(5):544-547.
[10] ABDURRAHMAN E,YILDIRAY K,HABIB B. Histopathological effects of intramuscular metamizole sodium on rat sciatic nerve[J]. Iranian Journal of Basic Medical Sciences,2016,19(8):829.
[11]崔景斌,奚念朱,蒋新国.安乃近代谢物4-甲氨基安替比林的HPLC测定及其鼻腔滴剂在人体的相对生物利用度[J].药学学报,1997,32(1):65-68.
[12]SITARIST N,POLA W,WOLHOFF H. Thin-layer chromatographic determination of major metamizole metabolites in serum and urine[J]. Journal of Chromatography B:Biomedical Sciences and Applications,1983,274:289-298.
[13] BURMANCZUK A,KOWALSKI C,GIORGI M,et al.Pharmacokinetic investigations of the marker active metabolites 4-methylamino-antipyrine and 4-amino-antipyrine after intramuscular injection of metamizole in healthy piglets[J]. Journal of Veterinary Pharmacology and Therapeutics,2016,39(6):616-620.
[14]国家食品药品监督管理局.化学药物急性毒性试验技术指导原则[S].北京,2005.
[15]ADRIANA A,ELENA G M,MARIA S,et al. Pyrazolones metabolites are relevant for identifying selective anaphylaxis to metamizole[J]. Scientific Reports,2016,31(6):1-9.
[16]LEVY M,FLUSSER D,ZYLBER-KATZ E,et al. Plasma kinetics of dipyrone metabolites in rapid and slowacetylators[J]. European Journal of Clinical Pharmacology,1984,27(4):453-458.
[17]MARKUS H,HAGEN G,KARL T,et al. Selective venous vasodilator properties of the analgesic metamizole(dipyrone)in a human ex vivo model—implications for postoperative pain management[J]. Naunyn-Schmiedeberg's Arch Pharmacol,2017,390(5):519-526.
[2]国家药典委员会.中华人民共和国药典:二部[M].北京:中国医药科技出版社,2010:286.
[3]国家药典委员会.中华人民共和国药典:第一增补本[M].北京:中国医药科技出版社,2010:286-287,361-362.
[4]国家药典委员会.临床用药须知[M].北京:人民卫生出版社,2005:721-722.
[5]陈新谦,金有豫,汤光.新编药物学[M]. 17版.北京:人民卫生出版社,2011:200.
[6]谢先飞,曾繁典.安乃近不良反应及急性中毒事件的文献分析[J].药物流行病学杂志,2002,11(4):182-184.
[7] ARONSON J K. MEYLER药物副作用[M].北京:科学出版社,2007:2268-2269.
[8]雷光远,雷招宝.安乃近致死亡26例分析[J].医药导报,2012,31(11):1517-1521.
[9] HASSAN K,KHAZIM K,HASSAN F,et al. Acute kidney injury associated with metamizole sodium ingestion[J]. Renal Failure,2011,33(5):544-547.
[10] ABDURRAHMAN E,YILDIRAY K,HABIB B. Histopathological effects of intramuscular metamizole sodium on rat sciatic nerve[J]. Iranian Journal of Basic Medical Sciences,2016,19(8):829.
[11]崔景斌,奚念朱,蒋新国.安乃近代谢物4-甲氨基安替比林的HPLC测定及其鼻腔滴剂在人体的相对生物利用度[J].药学学报,1997,32(1):65-68.
[12]SITARIST N,POLA W,WOLHOFF H. Thin-layer chromatographic determination of major metamizole metabolites in serum and urine[J]. Journal of Chromatography B:Biomedical Sciences and Applications,1983,274:289-298.
[13] BURMANCZUK A,KOWALSKI C,GIORGI M,et al.Pharmacokinetic investigations of the marker active metabolites 4-methylamino-antipyrine and 4-amino-antipyrine after intramuscular injection of metamizole in healthy piglets[J]. Journal of Veterinary Pharmacology and Therapeutics,2016,39(6):616-620.
[14]国家食品药品监督管理局.化学药物急性毒性试验技术指导原则[S].北京,2005.
[15]ADRIANA A,ELENA G M,MARIA S,et al. Pyrazolones metabolites are relevant for identifying selective anaphylaxis to metamizole[J]. Scientific Reports,2016,31(6):1-9.
[16]LEVY M,FLUSSER D,ZYLBER-KATZ E,et al. Plasma kinetics of dipyrone metabolites in rapid and slowacetylators[J]. European Journal of Clinical Pharmacology,1984,27(4):453-458.
[17]MARKUS H,HAGEN G,KARL T,et al. Selective venous vasodilator properties of the analgesic metamizole(dipyrone)in a human ex vivo model—implications for postoperative pain management[J]. Naunyn-Schmiedeberg's Arch Pharmacol,2017,390(5):519-526.