隨著3Rs原則的實施,藥物非臨床生殖發(fā)育毒性研究中的整體動物試驗面臨嚴(yán)重挑戰(zhàn),體外替代研究逐步成為研究熱點。生殖發(fā)育毒性周期長,涵蓋面廣,現(xiàn)有的任何一種體外方法無法全面模擬藥物在體內(nèi)作用的全過程,無法全面反映其對于生殖發(fā)育周期中性成熟、受精、配子發(fā)生、合子發(fā)育、出生后發(fā)育及性功能等方面的影響。形成一套完整的生殖發(fā)育毒性體外替代法評價是解決體外替代法預(yù)測結(jié)果接近體內(nèi)檢測結(jié)果的關(guān)鍵,在整合體外替代研究時,應(yīng)考慮體細(xì)胞與生殖細(xì)胞,不同進(jìn)化階段的物種,多個生殖毒性周期,體內(nèi)外代謝活化差異等因素。根據(jù)受試物特性、分布、用途、適用范圍,其他毒理學(xué)實驗及毒代動力學(xué)資料,技術(shù)水平,管理部門的要求等特點進(jìn)行實驗設(shè)計,通過一系列反應(yīng)不同試驗終點的組合實驗(Integrated testing strategy,ITS)綜合評定藥物體外生殖發(fā)育毒性,但目前尚無最合理的組合方案。對生殖發(fā)育毒性體外試驗研究進(jìn)展及應(yīng)用策略需考慮要點進(jìn)行綜述,以推動替代技術(shù)在藥物非臨床安全性評價中的應(yīng)用。

With the implementation of the 3Rs principle, the non-clinical reproductive and developmental toxicity studies of drugs in experimental animals are facing great challenges. Due to the long period of reproductive and developmental toxicity, any of the existing in vitro method cannot fully simulate the whole process of drug action in vivo. The existing methods cannot fully reflect the development cycle for reproductive neutral maturation, fertilization, zygote development, impact of development and other aspects of sexual function after birth. It is necessary to form a complete set of alternative method for reproductive and developmental toxicity in vitro evaluation to solve the above problems. To design an integrate research of in vitro alternative methods, the researchers should consider somatic and germ cells in different stages of the evolution of species, a number of reproductive toxicity periods, in vivo metabolic activation differences, and other factors. According to characteristics, distribution, use, scope, other toxicology experiments and toxic kinetic information, technology, management and other characteristics of the test substance, the experiment design requires a series of reactions with different combinations of experimental study endpoint (integrated testing strategy, ITS) of comprehensive assessment of reproductive and developmental toxicity in vitro drug. There is no combination of the most reasonable scheme available. In this paper, we will discuss the latest progress of in vitro studies and how to promote a battery of alternative technology of developmental and reproductive toxicity in the pharmaceutical non-clinical safety evaluation.

中國食品藥品檢定研究院中青年發(fā)展研究基金(2014C2)