目的 建立黃芪六一湯藥效組分（黃芪總皂苷、黃芪總黃酮、黃芪多糖、甘草酸組成，HLDC）抗糖尿病腎病的藥動學(xué)（PK）-藥效動力學(xué)（PD）結(jié)合模型，闡明HLDC成分在糖尿病腎病大鼠體內(nèi)的動態(tài)變化及與藥效消長之間的相互關(guān)系。方法 采用高脂高糖飼料及尾iv鏈脲佐菌素（33 mg·kg^-1）方法建立糖尿病腎病大鼠模型。單次或多次igHLDC（1.320 g·kg^-1）后，采用HPLC-MS/MS測定不同時間點血漿中黃芪甲苷、芒柄花苷、芒柄花素、毛蕊異黃酮葡萄糖苷、毛蕊異黃酮和甘草酸6個入血原型成分的含量，并采用酶聯(lián)免疫吸附法（ELISA）檢測定不同時間點血樣中腫瘤壞死因子-α （TNF-α）、血管內(nèi)皮生長因子（VEGF）、白細胞介素-18 （IL-18）等炎癥因子水平，獲得時效曲線。并利用WinNonlin 8.2軟件房室模型分析法擬合各成分的PK參數(shù)，固定PK，對時效關(guān)系進行擬合，得到PD；根據(jù)PD參數(shù)建立HLDC的PK-PD模型。結(jié)果 藥動學(xué)結(jié)果顯示，與單次給藥相比，除了毛蕊異黃酮葡萄糖苷外，多次給藥后模型大鼠的各成分的達峰時間（t_max）均提前；各成分的t_1/2均延后；除了甘草酸、毛蕊異黃酮外，各成分的AUC均升高。藥效學(xué)結(jié)果顯示，藥物質(zhì)量濃度逐漸降低的同時，藥物的抑制作用先增大后減小，除了單次給藥組中的黃芪甲苷，TNF-α、VEGF、IL-18的藥物效應(yīng)t_max均較血藥濃度t_max長，存在滯后效應(yīng)。PK-PD結(jié)合模型顯示，單次及多次給藥HLDC中6個成分的血藥濃度與其藥效數(shù)據(jù)均能較好地擬合。可通過黃芪甲苷等6個成分的血藥濃度計算相應(yīng)的藥效值，也可以根據(jù)藥效值計算相應(yīng)的血藥濃度。結(jié)論 PK-PD模型構(gòu)建結(jié)果符合Sigmoid-Emax模型，TNF-α、VEGF、IL-18等炎癥因子水平與HLDC中的黃芪甲苷等6個成分血藥濃度有良好的相關(guān)性。HLDC活性成分發(fā)揮防治糖尿病腎病、顯著改善腎功能的作用，可能與抑制TNF-α、VEGF、IL-18等炎癥因子的分泌有關(guān)。

Objective The PK-PD binding model of effective component (total astragaloside, total flavonoids of astragalus, astragalus polysaccharide, and glycyrrhizic acid, HLDC) of Huangqi Liuyi Decoction against diabetic nephropathy was established, and the dynamic changes of HLDC component in diabetic nephropathy rats and the relationship between HLDC component and drug effect were clarified. Methods The rat model of diabetic nephropathy was established by high-fat and high-sugar feed and streptozotocin (33 mg· kg^-1) injected into the tail vein. After single or multiple oral administrations of HLDC (1.320 g· kg^-1), the plasma contents of astragaloside IV, ononin, formononetin, calycosin-7-O-beta-D-glucoside, calycosin and glycyrrhizic acid were determined by HPLCMS/MS at different time points, and tumor necrosis factor-α (TNF-α), vascular endothelial growth factor (VEGF) and interleukin were detected by enzyme-linked immunosorbent assay (ELISA). The pharmacokinetic (PK) parameters of each component were fitted by using WinNonlin 8.2 software, and the aging relationship was fitted to get PD. The PK-PD model of HLDC is established according to PD parameters. Results The results of pharmacokinetics showed that compared with a single administration, the t_max of each component of the model rats was advanced after repeated administration except calycosin-7-O-beta-D-glucoside. T_1/2 of each component was delayed. Except glycyrrhizic acid and calycosin, the AUC of all components increased. The pharmacodynamic results showed that the inhibitory effect of the drug increased first and then decreased while the drug concentration gradually decreased. Except for astragaloside IV, TNF-α, VEGF, and IL-18 in the single-dose group, the peak time of the drug effect was longer than that in the blood concentration, and there was a lag effect. PK-PD binding model showed that the blood concentration of six components in single and multiple doses of HLDC and their pharmacodynamic data could be well fitted. The corresponding drug effect value can be calculated by the blood concentration of six components such as astragaloside IV, and the corresponding blood concentration can also be calculated according to the drug effect value. Conclusion The results of the PK-PD model are by the Sigmoid-Emax model, and the levels of inflammatory factors such as TNF-α, VEGF, and IL-18 have a good correlation with the concentrations of six blood component drugs such as astragaloside IV in HLDC. The active components of HLDC play a role in preventing and treating diabetic nephropathy and significantly improving renal function, which may be related to inhibiting the secretion of inflammatory factors such as TNF-α, VEGF, and IL-18.

R285.5

貴州省衛(wèi)生健康委科學(xué)技術(shù)基金項目（黔衛(wèi)健函〔2024〕24號）;貴州省科技計劃項目（黔科合基礎(chǔ)-ZK［2023］一般416）;2023年度貴州中醫(yī)藥大學(xué)學(xué)術(shù)新苗項目（貴科合學(xué)術(shù)新苗［2023］-13號）