雌性大鼠细胞色素P4503A酶诱导模型建立与验证

Establishment and Verification of Cytochrome P450 3A Enzyme Induction Model in Female Rats

目的建立雌性大鼠CYP3A酶诱导模型,用于CYP3A酶介导的药物-药物相互作用研究。方法 标准喂养的雌性SD大鼠18只随机分为两组,一组为空白对照组(3只),一组为实验组(15只分为5组)。实验组分别用20、50、80、100、150 mg·kg-1·d-1地塞米松连续灌胃3 d诱导CYP3A酶,灌胃3 d后的24 h,分别取两组大鼠的肝组织制备肝微粒体,以睾酮为探针底物,测定CYP3A4酶活性。结果 空白肝微粒体中睾酮代谢率为31.68%,地塞米松诱导组中睾酮代谢率为40.64%、61.36%、82.44%、85.8%、83.36%,经80 mg·kg-1·d-1地塞米松诱导后大鼠睾酮代谢率提高达160.23%。结论以地塞米松80 mg·kg-1·d-1的剂量诱导SD大鼠能够显著增加大鼠肝内CYP3A酶的活性,可用于研究CYP3A酶介导的药物-药物相互作用。

OBJECTIVE To establish a female rat CYP3A induction model which is used for studying CYP3A-mediated drug-drug interactions. METHODS Female SD rats which were fed with standard diet were randomly divided into two groups, one was the control group, and the other one was the experimental group. The rats in the experimental group were administered respectively 20, 50, 80, 100, and 150 mg. kg^-1 . d^-1 dexamethasone by gavage for 3 d to induce CYP3A enzymes. 24 h after 3 d, liver tissues were taken from both groups of rats and rat liver mierosomes were prepared. CYP3A4 activity was determined with testosterone as the probe substrate. RESULTS Testosterone metabolic rate was 31.68% in blank liver microsomes, and were 40. 64% , 61.36% , 82. 44% , 85.8% , and 83.36% in dexamethasone-induction group. Testosterone metabolic rate was improved by up to 160. 23% after dexam- ethasone induction at 80 mg . kg^-1 . d^-1 in female rats. CONCLUSION Dexamethasone induction at 80 mg . kg^-1 . d^-1 can significantly increase liver CYP3A enzyme activity in female SD rats, and the model can be used to study CYP3A-mediated drug-drug interactions.