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目的:研究注射用伏立康唑前药(FLKZQY)在雌、雄大鼠中代谢及毒性差异,并观察SD大鼠体内性激素水平的变化对伏立康唑前药在大鼠体内代谢的影响,为其进一步临床应用提供依据。方法:选取5~6周龄SD大鼠,随机分成去势与伪手术组,雌、雄分开分组(雌、雄各半,每组8只),手术后恢复3 d,然后连续7 d静脉注射120 mg·kg-1·d-1伏立康唑前药,于第7天进行眼眶采血。采用毒代动力学试验、酶联免疫吸附试验(ELISA)法,检测其代谢及毒性差异。结果:毒代动力学结果显示,伪手术雌鼠药时曲线下面积(AUC)、最大血药浓度(Cmax)、半衰期(t1/2)均高于伪手术雄鼠;去势雌鼠最大血药浓度(Cmax)、半衰期(t1/2)均较伪手术雌鼠显著性降低(P<0.05),药时曲线下面积(AUC)极其显著性降低(P<0.01);去势雄鼠受试物组与伪手术雄鼠受试物组相比药时曲线下面积(AUC)、半衰期(t1/2)、最大血药浓度(Cmax)则升高,其中AUC与Cmax差异显著(P<0.05);ELISA结果显示中,与伪手术雌鼠相比,去势雌鼠的肝脏细胞色素P450同工酶CYP2C19、CYP2C9以及CYP3A4含量均明显增加(P<0.05),去势雄鼠与伪手术雄鼠相比P450同工酶含量降低,但未达到统计学差异。结论:在本试验条件下,注射用伏立康唑前药在雌、雄大鼠体内的代谢存在性别差异。而性激素水平可能通过调节伏立康唑相关代谢酶水平从而对伏立康唑代谢产生影响。
OBJECTIVE: To study the metabolism and toxicity of voriconazole prodrug (FLKZQY) for injection in female and male rats and to observe the effect of voriconazole prodrug on the metabolism of voriconazole prodrug in rats for its further clinical application in accordance with. Methods: Sprague-Dawley rats aged 5 to 6 weeks were randomly divided into sham-operation group and sham operation group. Female and male rats were divided into three groups (female and male, 8 in each group). After 3 days, 120 mg · kg -1 · d -1 voriconazole prodrug was injected, and orbital blood was collected on the 7th day. Toxicokinetic tests and enzyme-linked immunosorbent assay (ELISA) were used to detect the differences in metabolism and toxicity. Results: Toxicokinetic results showed that the area under the curve (AUC), the maximum plasma concentration (Cmax) and the half-life (t1 / 2) (Cmax), half-life (t1 / 2) were significantly lower than those in sham operation group (P <0.05), and the area under the curve was significantly decreased (P <0.01) The area under the curve (AUC), half-life (t1 / 2), and maximum plasma concentration (Cmax) of the test substance group and the sham-operated male test substance group were significantly increased, 0.05). The results of ELISA showed that the content of cytochrome P450 isoenzyme CYP2C19, CYP2C9 and CYP3A4 in ovariectomized female rats were significantly increased (P <0.05) Compared with the P450 isozymes in male rats decreased, but did not reach statistical significance. Conclusion: Under the conditions of this test, there is a gender difference in the metabolism of voriconazole prodrug in female and male rats. However, the level of sex hormones may affect the metabolism of voriconazole by regulating the level of voriconazole-related metabolic enzymes.