Jiannong Wang, Junjie Jiang, Yanming Xie, Xu Wei, Jianpeng Li, Jingli Duan, Xin Xiong
J Tradit Chin Med. 2015 Apr;35(2):141-53. doi: 10.1016/s0254-6272(15)30021-2.
To characterize naringenin (NAR) pop- ulation pharmacokinetics (PPK) in Chinese women with primary osteoporosis.
Ninety-eight female patients with primary osteoporosis from the Jingshan, Beixinqiao, Jiaodaokou, Chaoyangmen, and Donghuamen communities in Beijing, China, aged 40 to 80 years, re- ceived oral Qianggu capsules (250 mg). Blood samples were collected before and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 24 h after administration. The concentration of NAR in the blood samples was measured using high performance liquid chromatography-tandem mass spectrometry. PPK analyses were performed with nonlinear mixed-effect modeling software (version 7.1.2, PsN3.2.12). The clearance (C1), central distribution volume (V), absorption rate constant (Ka1), peripheral distribution volume (VII), and inter-compartmental clearance (CLII) were set as parameters and estimated by the base model, covariate model, and final model. Kidney-Yang deficiency [Shenyangxu (SYAX)] and liver-kidney-Yin deficiency (Ganshenyinxu) are patterns of symptoms in Traditional Chinese Medicine that were set as covariates, along with age, height, blood urea nitrogen, serum creatinine, alanine transaminase, aspartate transaminase, and hyperlipidemia. Both stepwise forward and backward procedures were accomplished to build models. The final model was evaluated by internal and external validation, visual predictive check, bootstrap, and leverage analysis.
A one compartment open model with first order degradation was the best fitted to the concentration-time profiles following oral administration of NAR. The mean of population parameters of the final model, C1, SYAX on C1, V, Ka1, CLII, and VII, were measured to be 37.6 L/h, 0.427 L, 123 L/h, 0.12/h, 0.3056, and 1.446, respectively. Inter-individual variability was estimated and SYAX was identified as a significant covariate.
The population pharmacokinetic model described in this study could effectively characterize the pharmacokinetic profile of NAR following administration of a single dose of oral Qianggu capsules in Chinese women with primary osteoporosis. Among the tested covariates, only SYAX was a significant factor.
描述柚皮素（NAR）在中国原发性骨质疏松症女性中的群体药代动力学（PPK）特征。
98例年龄在40至80岁之间的中国北京景山、北新桥、交道口、朝阳门和东华门社区的原发性骨质疏松症女性患者，口服强骨胶囊（250mg）。在给药前及给药后0.5、1、2、3、4、6、8、10、12和24小时采集血样。采用高效液相色谱-串联质谱法测定血样中NAR的浓度。使用非线性混合效应建模软件（版本7.1.2，PsN3.2.12）进行PPK分析。将清除率（C1）、中央分布容积（V）、吸收速率常数（Ka1）、外周分布容积（VII）和隔室间清除率（CLII）设定为参数，并通过基础模型、协变量模型和最终模型进行估计。肾阳虚[沈阳虚（SYAX）]和肝肾阴虚是中医症状类型，与年龄、身高、血尿素氮、血清肌酐、丙氨酸转氨酶、天冬氨酸转氨酶和高脂血症一起设定为协变量。采用逐步向前和向后程序构建模型。通过内部和外部验证、可视化预测检查、自抽样法和杠杆分析对最终模型进行评估。
口服NAR后，一室开放一级降解模型最适合浓度-时间曲线。最终模型的群体参数均值，C1、SYAX对C1的影响、V、Ka1、CLII和VII，分别测得为37.6L/h、0.427L、123L/h、0.12/h、0.3056和1.446。估计个体间变异性，并确定SYAX为显著协变量。
本研究中描述的群体药代动力学模型可以有效地描述单剂量口服强骨胶囊后NAR在中国原发性骨质疏松症女性中的药代动力学特征。在测试的协变量中，只有SYAX是一个显著因素。
