慢性肾脏疾病（CKD）不仅影响药物的经肾消除还影响药物代谢酶的活性。研究表明CKD时肝脏CYP3A4代谢酶活性显著下降，但量效关系及具体机制不明，难以临床转化应用。近期研究显示，CKD患者血清中甲状旁腺激素（PTH）水平的升高是引起肝脏CYP3A4下调的主要因素，本课题组前期研究也发现外源性PTH可下调原代大鼠肝细胞中CYP3A1和CYP3A2（人CYP3A4直系同源酶）的表达且其作用可能存在量效关系。因此，本项目将通过体内外实验研究PTH对CYP3A4影响的量效关系；采用Real-time PCR、Western Blot及基因敲除动物模型等研究CKD时PTH下调CYP3A4的分子机制；最后建立基于PTH水平的个体化给药群体药动/药效学模型，并在临床患者中验证与应用仿真模型。本研究不仅为CKD患者个体化用药提供理论依据和临床指导，还为CKD特殊人群药物相互作用和药物开发提供理论指导。

Chronic kidney disease (CKD) affects not only drugs’ renal elimination but also the activity of drug metabolizing enzymes. Studies have shown that the activity of cytochrome P450 3A4 are significantly decreased in CKD, but the dose-response relationship and specific mechanism remain unknown, which unable to be used for clinical transformational applications. Recent literature reports that the elevated serum level of parathyroid hormone (PTH) in patients with CKD can mainly explain for the down-regulation of activity of hepatic CYP3A4. Our pilot study also found that the expression of CYP3A1 and CYP3A2 ( Rat CYP3A1 and CYP3A4 correspond to human CYP3A4) in primary cultured rat hepatocytes were down-regulated by PTH possibility with a dose-response relationship. Therefore, we will investigate the dose-response relationship of PTH and CYP3A4 by in vivo and in vitro studies in our project; Then further explore the mechanism of PTH down-regulating the activity of CYP3A4 in CKD by techniques of Real-time PCR, Western Blot, Gene knockout technology and so on; Finally establish the population pharmacokinetic/pharmacodynamic model for individualizing dosage regimens based on the level of PTH, and verify the model and apply it to clinical practice. Our research will not only provide the theoretical basis and clinical guidelines for personalized medicine of CKD patients, but also provide the theoretical guidance for drug interaction studies and drug development in CKD special populations.