以异丙酚作为工具药基于单心室循环建立混杂生理药代药效学模型

Our previous study failed to validate clinically the accuracy of application of effect-site elimination rate constant derived from the time to peak effect time to predict early phase phararmacodynamics of propofol, which might be related to the inherent limitations of traditional compartment model. Based on population pharmacokinetic modeling methods, we found that the pharmacokinetics of etomidate was best estimated using a three-compartment model with allometric scaling of weight on volumes and clearances. Age was a significant covariate of systemic clearance with increasing age having decreasing clearance in children. Our further study confirmed that central distribution volume of etomidate was larger in congenital heart disease with left to right shunt compared with health children, and to lesser extent, systemic clearance was decreased. As a result, we further suspect that the pharmacokinetics and/or pharmacodynamics might be more complex in the pediatric patients with single ventricle, which have a huge anatomical difference from the "normal" circulation system. Given the distribution of drugs in the body can not be separated from the circulation system and it is difficult to clarify the precise mechanism of pharmacokinetic changes caused possibly by single ventricle circulation with the traditional compartment model. Moreover, there was limited information about the effect of anesthesia on single ventricle circulation. The present project is designed to estabolish lumping (hybrid) physically-based pharmacokinetic-pharmacodynamic model (PBPK/PD) of propofol with anatomical and physical data of corresponding disease states acquired from experimental animal based on the anatomy, physiology and development of stage surgery (Glenn and Fontan operation) for single ventricle pediatric patients. Subsequently, the structure and characteristics of PBPK model, the effect of drug administration regimen on drug distribution in the body, and pharmacodynamic change will be clarified with computer simulation. Finally, anesthesia optimization strategies will be suggested on basis of PBPK/PD model in single ventricle pediatric patients.

我们未能证实根据峰效应时间计算的效应室消除速率常数预测异丙酚早期药效学的准确性，可能与传统房室模型的固有局限性有关。基于群体建模方法发现小儿依托咪酯药代学可用三室异速生长模型描述，年龄增加清除率降低；随后又发现先心左向右分流增加了该药的中央室容积，清除率也一定程度上降低。由此我们进一步猜想，单心室等复杂先心患儿循环系统与正常差异巨大，药代药效学可能更为复杂。鉴于药物体内分布离不开血液循环，房室模型又很难阐明单心室分期手术特殊解剖可能导致的药代学改变机制，且麻醉药影响单心室循环的资料有限。本课题以异丙酚为工具药，基于单心室患儿分期手术（Glenn和Fontan手术）的解剖、生理和发育，利用动物模型获得相应疾病状态下的生理数据并建立混杂药代药效学（PBPK/PD）模型。随后借助计算机模拟，阐明模型的结构和特点、用药方式对药代学的影响以及相应的药效学变化。最终形成单心室患儿麻醉优化策略。

先天性心脏病患儿分期手术后心血管解剖导致其血液循环与“正常”人体有巨大差异，疾病进程也影响着器官功能，进而影响麻醉药的药代学药效学。因此，建立基于解剖、生理和疾病状态下的生理药代药效学模型（PBPK/PD）可能有助于阐明各种用药方式对体内药物分布的影响以及相应的药效学变化。基于上述思路完成了以下内容：⑴正常和存在左向右分流的先天性心脏病患儿单次注射依托咪酯的群体药代学分析。研究证实婴儿依托咪酯的药代动力学可用三房室模型描述；基于异速生长模型，体重是显著影响婴儿依托咪酯药代动力学的唯一因素。先天性心脏病不改变0～1岁患儿依托咪酯的药代动力学；⑵首次描述了未修补的法乐氏四联症患儿用依托咪酯麻醉时的药代动力学特点。与心脏解剖正常的患儿相比，先天性心脏病患儿中央室清除率显著降低；⑶基于非线性混合效应模型，我们也系统分析了成人和小儿瑞芬太尼的药代学特点，证实生长发育和疾病的差异，并不影响瑞芬太尼的药代学；⑷基础研究方面，证实生命早期受到疼痛刺激后，疼痛的敏感性增加，这种敏感性增加可能与脊髓IL-1和TNF-的增加有关，而锻炼可消除这种增加，并减少新生期受伤引起的疼痛敏感性（超敏）增加；证实梗阻性黄疸时大鼠对丙泊酚的麻醉敏感性增加，且随着梗阻时间的延长有逐渐增加的趋势；胆道梗阻解除后增高的麻醉敏感性会逐渐恢复；⑸探索了使用多巴胺等心血管活性药物是否可以改善单心室先心患儿需多次手术而可能由麻醉药诱发神经细胞凋亡，结果证实多巴胺D1、D2、A2A受体激活通过上调cAMP / PKA信号通路对乙醇诱导的发育大鼠视网膜神经节细胞层的细胞凋亡具有保护性作用；⑹临床探讨了梗阻性黄疸对静脉麻醉中丙泊酚用量的影响。结果证实梗阻性黄疸患者在静脉麻醉中可减少丙泊酚用量；⑺比较生物电抗法和双平面二维超声法在小儿室间隔缺损患者与心脏解剖正常患儿麻醉诱导中心输出量监测的一致性。