Developmental toxicity of zopiclone and its impurities in zebrafish embryos

doi:10.19803/j.1672-8629.2022.01.12

Abstract

Abstract: Objective To compare the toxicity of zopiclone and its main impurities on embryonic development of zebrafish. Methods Embryonic development of zebrafish was investigated under a stereo microscope at different concentrations of the drug. The teratogenicity and lethality of zebrafish embryos were statistically analyzed in conjunction with microscopic observation. Results Zopiclone and its impurities had a similar toxic phenotype to embryonic development of zebrafish and the toxic effects occurred during the development of embryonic organs. The results showed that both teratogenicity and the mortality rate of embryos were positively correlated with drug concentrations. The embryonic toxicity was the strongest in impurity C, followed by 2-amino-5-chloropyridine, impurity B, impurity A, and zopiclone. Conclusion Based on the impurity spectrum of zopiclone, the contents of impurities in marketed drugs and the experimental toxicity results of zopiclone and its major impurities on embryonic development, it was recommended that 2-amino-5-chloropyridine be controlled as a specified impurity with a strict limit in the quality specifications of zopiclone materials and preparations in order to ensure the safety and quality of this drug.

Key words: zopiclone, impurities, zebrafish embryo, developmental toxicity, toxicity comparison, 2-amino-5-chloropyridin

CLC Number:

R927

YIN Jie, NAN Nan, CHEN Hua. Developmental toxicity of zopiclone and its impurities in zebrafish embryos[J]. Chinese Journal of Pharmacovigilance, 2022, 19(1): 57-61.

References

[1] ZHANG Y, GUO SY, DENG ZP, et al.Zebrafish used in toxic target organ studies of Chinese herbs[J]. Chinese Journal of New Drugs(中国新药杂志), 2016, 25(12): 1343-1347.
[2] XU BJ, ZHANG LJ, LI CQ, et al.Evaluation of developmental toxicity and model validation of five drugs in zebrafish embryos[J]. Chinese Pharmacological Bulletin(中国药理学通报), 2016, 32(1): 74-79.
[3] MITTELSTADT SW, HEMENWAY CL, CRAIG MP, et al.Evaluation of zebrafish embryos as a model for assessing inhibition of hERG[J]. Journal of Pharmacological and Toxicological Methods, 2008, 57(2): 100-105.
[4] ZHU JJ, XU YQ, HE JH, et al.Human cardiotoxic drugs delivered by soaking and microinjection induce cardiovascular toxicity in zebrafish[J]. Journal of Applied Toxicology, 2014, 34(2): 139-148.
[5] CHANG J, LU L, WANG QL, et al.Progress of application of zebrafish in early drug toxicology screening[J]. Chinese Journal of New Drugs(中国新药杂志), 2013, 22(13): 1500-1504.
[6] LIANG AH.Zebrafish-a fish model for screening efficacy and toxicity of traditional Chinese Medicine[J]. China Journal of Chinese Material Medica(中国中药杂志), 2009, 34(22): 2839-2842.
[7] GUO J, GENG XC, WANG JF.Research progress and integrated testing strategies on alternative methods in drug developmental toxicity evaluation[J]. Drug Evaluation Research(药物评价研究), 2015, 38(4): 345-349.
[8] TONG JW, ZHANG JP, MENG J.Teratogenesis and gene targets of 17α-ethynylestradiol on embryonic development in zebrafish[J]. Acta Pharmaceutica Sinica(药学学报), 2011, 46(1): 50-55.
[9] HU ZY, ZHANG JP.Effects of vincristine on zebrafish neurodevelopment and behavior[J]. Journal of Toxicology(毒理学杂志), 2014, 28(12): 98-103.
[10] DIAV-CITRIN O, OKOTORE B, LUCARELLI K, et al.Zopiclone use during pregnancy[J]. Can Fam Physician, 2000, 46: 63-64.
[11] OKUN ML, EBERT R, SAINI B.A review of sleep-promoting medications used in pregnancy[J]. Am J Obstet Gynecol, 2015, 212(4): 428-441.
[12] DIAV-CITRIN O, OKOTORE B, LUCARELLI K, et al.Pregnancy outcome following first-trimester exposure to zopiclone: a prospective controlled cohort study[J]. Am J Perinatol, 1999, 16(4): 157-160.