探索枸橼酸坦度螺酮中可能存在的遗传毒性杂质,保障用药安全。方法 基于枸橼酸坦度螺酮合成工艺,结合遗传毒性杂质警示结构、计算机毒理学预测及Ames试验判断其杂质遗传毒性分类。结果 1,4-二溴丁烷具有致突变性,为枸橼酸坦度螺酮中存在的2类遗传毒性杂质。结论 1,4-二溴丁烷为枸橼酸坦度螺酮的2类遗传毒性杂质,应在药物中严格控制其残留量,以保障用药安全。
Abstract
To explore the possible genotoxic impurities in tandospirone citrate to ensure the safety of medication. METHODS Based on the synthesis process of tandospirone citrate, combined with the warning structure of genotoxic impurities, computer toxicology prediction and Ames test, the classification of genotoxicity of impurities was determined. RESULTS 1,4-dibromobutane was mutagenic, which was a class 2 genotoxic impurities in tandospirone citrate. CONCLUSION 1,4-dibromobutane is a class 2 genotoxic impurity of tandospirone citrate, and its residue should be strictly controlled in the drug to ensure the safety of medication.
关键词
枸橼酸坦度螺酮 /
计算机毒理学预测 /
细菌回复突变试验 /
遗传毒性杂质
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Key words
tandospirone citrate /
computational toxicology assessment /
Ames test /
genotoxic impurity
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中图分类号：
R917
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参考文献
[1] WU C J, LI Q, LU Y T. A comparative study of tandospirone combined with antidepressants in the treatment of depression [J]. Med J Chin People Health (中国民康医学),2013,25(17):33-34.
[2] BENIGNI R, BOSSA C, TCHEREMENSKAIA O, et al. Development of structural alerts for the in vivo micronucleus assay in rodents [J]. Eur Comm, 2009: 1-43.
[3] SUN B H, LI W L, GUAN H Y, et al. Research progress of genotoxic impurities in generic drugs [J]. Clin Med J(临床药物治疗杂志), 2022, 20 (2):8-12.
[4] JACEK C, ZDZISLAW C, WIESLAW S, et al. An efficient synthesis of buspirone and its analogues [J]. Arch Pharm (Weinheim), 1992, 325(5), 313–315.
[5] ISHIZUMI K, KOJIMA A, ANTOKU F. Synthesis and anxiolytic activity of N-substituted cyclic imides (1R*, 2S*, 3R*, 4S*)-N-[4-[4-(2-pyrimidinyl)-1-piperazinyl] butyl]-2, 3-bicyclo [2.2.1] heptanedicarboximide (tandospirone) and related compounds [J]. Chem Pharm Bull(Tokyo), 1991, 39(9):2288-2300.
[6] CHEN G Z, HU H P, WANG Y C, et al. Tandospirone citrate and its preparation method, preparation and quality control method: China, 201010211298.2 [P]. 2010-11-10.
[7] GARY D, MADDING. Process for preparing certain azapirones: United States, 5521313 [P]. 1996-05-28.
[8] WOCOLOMBANO G, BARBERO, M, GIOVENZANA G, et al. Processfor the synthesis of gepirone: World Intellectual Property Organization, 2020/148621 A1 [P]. 2020-07-23.
[9] KIKUO I, FUJIO A, YUKIO A. Succinimide derivatives, compositions and method of use: United States, 4507303 [P]. 1985-03-26.
[10] ZHANG J S, LI L. A Preparation Method of Tandospirone and Its Analogues: China, 201010211298.2 [P]. 2010-11-10.
[11] LI J, HE L L, QIU L Y, et al. Determination of contents and related substance in citrate tandospirone tablets by HPLC [J]. J Southwest Minzu Univ (Nat Sci Ed) (西南民族大学学报 自然科学版), 2016, 42 (2):183-187.
[12] HE X Y, LI L, BAO W J, et al. Study on related substances of tandospirone citrate capsules [J]. Xihua Univ Nat Sci (Nat Sci Ed) (西华大学学报 自然科学版), 2011, 30 (4):104-108.
[13] JAKUB T, ROBERT S. Photolytic and photocatalytic degradation of tandospirone: Determination of kinetics, identification of transformation products and in silico estimation of toxicity [J]. Sci Total Environ, 2017, 590-591:775-798.
[14] ICH M7(R1). Assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk [EB/OL]. (2015-06-09). [2022-05-16]. https://www.fda.gov/media/156521/download.
[15] National Medical Products Administration. Technical guidelines for drug genetic toxicity research [EB/OL]. (2018-03-15). [2022-05-16]. https://www.nmpa.gov.cn/directory/web/nmpa/xxgk/ggtg/qtggtg/20180315160901208.html.
[16] CHEN L, ZHU Q F, JI W J, et al. Study on (Q)SAR evaluation and Ames test of mutagenicity of impurities in ceritinib [J]. Chin J Mod Appl Pharm(中国现代应用药学), 2021, 38(24):3082-3086.
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