Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, China.
Acta Pharmacol Sin. 2012 Jan;33(1):127-36. doi: 10.1038/aps.2011.161.
To develop a pharmacokinetic/pharmacodynamic (PK/PD) model describing the receptor/gene-mediated induction of CYP3A1/2 by dexamethasone (DEX) in rats.
A group of male Sprague-Dawley rats receiving DEX (100 mg/kg, ip) were sacrificed at various time points up to 60 h post-treatment. Their blood sample and liver were collected. The plasma concentration of DEX was determined with a reverse phase HPLC method. CYP3A1/2 mRNA, protein levels and enzyme activity were measured using RT-PCR, ELISA and the testosterone substrate assay, respectively. Data analyses were performed using a first-order conditional estimate (FOCE) with INTERACTION method in NONMEM version 7.1.2.
A two-compartment model with zero-order absorption was applied to describe the pharmacokinetic characteristics of DEX. Systemic clearance, the apparent volume of distribution and the duration of zero-order absorption were calculated to be 172.7 mL·kg(-1)·h(-1), 657.4 mL/kg and 10.47 h, respectively. An indirect response model with a series of transit compartments was developed to describe the induction of CYP3A1/2 via PXR transactivation by DEX. The maximum induction of CYP3A1 and CYP3A2 mRNA levels was achieved, showing nearly 21.29- and 8.67-fold increases relative to the basal levels, respectively. The CYP3A1 and CYP3A2 protein levels were increased by 8.02-fold and 2.49-fold, respectively. The total enzyme activities of CYP3A1/2 were shown to increase by up to 2.79-fold, with a lag time of 40 h from the Tmax of the DEX plasma concentration. The final PK/PD model was able to recapitulate the delayed induction of CYP3A1/2 mRNA, protein and enzyme activity by DEX.
A mechanism-based PK/PD model was developed to characterize the complex concentration-induction response relationship between DEX and CYP3A1/2 and to resolve the drug- and system-specific PK/PD parameters for the course of induction.
建立描述地塞米松（DEX）诱导大鼠 CYP3A1/2 受体/基因介导的药代动力学/药效动力学（PK/PD）模型。
一组雄性 Sprague-Dawley 大鼠（SD 大鼠）经腹腔（ip）给予 DEX（100mg/kg），在治疗后 60 小时内的不同时间点处死。采集血样和肝脏。采用反相高效液相色谱法（HPLC）测定 DEX 血浆浓度。采用逆转录聚合酶链反应（RT-PCR）、酶联免疫吸附测定（ELISA）和睾酮底物测定法分别测定 CYP3A1/2mRNA、蛋白水平和酶活性。数据采用 NONMEM 版本 7.1.2 中的一阶条件估计（FOCE）与 INTERACTION 方法进行分析。
采用零级吸收的二室模型描述 DEX 的药代动力学特征。计算得到 DEX 的系统清除率、表观分布容积和零级吸收持续时间分别为 172.7mL·kg(-1)·h(-1)、657.4mL/kg 和 10.47h。建立了一个间接反应模型，其中包含一系列过渡室，用于描述 DEX 通过 PXR 反式激活诱导 CYP3A1/2。CYP3A1 和 CYP3A2 mRNA 水平的最大诱导分别达到基础水平的 21.29 倍和 8.67 倍。CYP3A1 和 CYP3A2 蛋白水平分别增加了 8.02 倍和 2.49 倍。CYP3A1/2 总酶活性最高增加了 2.79 倍，在 DEX 血浆浓度的 Tmax 后 40 小时出现滞后时间。最终的 PK/PD 模型能够再现 DEX 对 CYP3A1/2mRNA、蛋白和酶活性的延迟诱导。
建立了一个基于机制的 PK/PD 模型，以描述 DEX 与 CYP3A1/2 之间复杂的浓度诱导反应关系，并确定诱导过程中药物和系统特异性的 PK/PD 参数。
