目的 對蘋果酸舒尼替尼的3個已知雜質進行（定量）構效關系計算機模型［（Q）SAR］評價，并對雜質E進行細菌回復突變（Ames）試驗研究。方法 根據(jù)國際人用藥品注冊技術協(xié)調會（ICH）M7指導原則的要求，采用基于專家知識規(guī)則的Derek和基于統(tǒng)計學的Sarah兩類（Q）SAR評價系統(tǒng)，對蘋果酸舒尼替尼的3個雜質——雜質v-7、雜質v-1及雜質E進行評價和分類。對于確定為遺傳毒性陽性的雜質E，采用Ames試驗進行驗證。結果 蘋果酸舒尼替尼的雜質v-7、雜質v-1預測結果為陰性，雜質E預測結果為陽性，且分類為3類。在加與不加S9的條件下，Ames試驗中雜質E8～5000μg·皿^-1質量濃度回復突變菌落數(shù)均未超過溶劑對照組的2倍，試驗結果為陰性。結論 蘋果酸舒尼替尼的3個雜質——雜質v-7、雜質v-1及雜質E均可以按照非遺傳毒性雜質進行控制。

Objective Three known impurities of Sunitinib malate were evaluated by (quantitative) structure-activity relationship computer model [(Q) SAR], and to study the impurity which was classified as class 3 by Ames test.Methods According to ICH M7 guidelines, two (Q)SAR prediction methodologies were applied(expert rule-based Derek and statistical-based Sarah) to assess and classify three impurities in Sunitinib malate (impurity v-7, impurity v-1 and impurity E). Ames test was used to verify impurity E which was confirmed as positive genotoxicity.Results (Q)SAR evaluation showed that impurity v-7 and impurity v-1 were nonmutagenic while impurity E was positive, which was classified as class 3. The results of Ames test indicated that the number of revertant colonies of test sample group was no more than twice of solvent control group induced revertant colonies and the test result represented negative at doses from 8 to 5 000 μg·plate^-1 with or without S9.Conclusion The three impurities of sunitinib malate --impurity v-7, impurity v-1 and impurity E can be controlled as non-genotoxic impurities.

R965.3