目的研究腎康注射液在正常和慢性腎衰大鼠體內的藥動學，為腎康注射液的臨床安全合理用藥提供科學參考。方法選擇黃芪甲苷和大黃酸作為腎康注射液的藥動學標記物，建立液相色譜-串聯(lián)質譜（LC-MS/MS）法檢測其血藥濃度，并進行專屬性、精密度、準確度、回收率、基質效應、穩(wěn)定性考察；采用連續(xù)21 d ig腺嘌呤（250 mg/kg）誘導大鼠慢性腎衰模型，觀察并記錄兩組大鼠的體質量、腎質量、尿量；全自動生化儀檢測血清肌酐（Cr）、尿素氮（BUN）水平，觀察腎臟外觀并進行組織切片HE染色處理。正常和慢性腎衰大鼠靜脈滴注腎康注射液（2 mL/kg），采用LC-MS/MS法測定大鼠血漿中黃芪甲苷和大黃酸的血藥濃度。結果 LC-MS/MS法采用Hypersil BDS-C₁₈（4.6 mm×150 mm，5 μm）色譜柱；流動相為乙腈-0.1%甲酸水（8：2）；體積流量0.8 mL/min；柱溫30℃；進樣量為10 μL；電噴霧離子源（ESI），負離子掃描檢測方式，動態(tài)多反應監(jiān)測模式（MRM）。方法學驗證結果表明，LC-MS/MS測定方法快速、靈敏、特異。ig腺嘌呤21 d后，與對照組比較，造模組腎臟肥大，顏色蒼白，造模組組織切片的腎小體數(shù)量減少、腎小球囊腔增大、腎小管內有棕色的腺嘌呤沉積。與對照組比較，從造模10 d起慢性腎衰大鼠的體質量顯著減輕（P<0.05）；造模結束后，腎質量顯著增加、24 h尿量顯著增加、血清肌酐和尿素氮水平顯著升高（P<0.05），慢性腎衰大鼠模型成功建立。大鼠藥動學實驗結果發(fā)現(xiàn)，與對照組比較，慢性腎衰大鼠體內黃芪甲苷的藥時曲線下面積（AUC_0-t）和最大血藥濃度（C_max）分別下降了28.6%和21.6%，黃芪甲苷和大黃酸的清除半衰期（t_1/2z）分別縮短了23.5%和43.7%，均具有統(tǒng)計學差異（P<0.05）。結論慢性腎衰大鼠對腎康注射液的清除加快，藥物作用時間縮短。

Objective Pharmacokinetics of astragaloside IV and rhein in normal and chronic renal failure rats were studied after intravenous injection of Shenkang Injection to provide useful information for the clinical rational drug use. Methods Astragaloside IV and rhein were selected as the pharmacokinetic markers of Shenkang Injection. A liquid chromatography tandem mass spectrometry (LC-MS/MS) method was established to detect the plasma concentration of Shenkang injection, and the specificity, precision, accuracy, recovery, matrix effect and stability were investigated. Chronic renal failure was induced by adenine (250 mg/kg) in rats. Rats received Shenkang Injection (2 mL/kg) intravenously. The body weight, kidney weight and urine volume of the two groups were observed and recorded, and the levels of serum creatinine (Cr) and urea nitrogen (BUN) were detected by automatic biochemical analyzer, and the appearance of kidney was observed and the tissue sections were stained with HE. Plasma concentrations of astragaloside IV and rhein were determined by LC-MS/MS. Results Hypersil BDS-C₁₈ (4.6 mm×150 mm, 5 μm) column was used. The mobile phase was acetonitrile-0.1% formic acid water (8: 2); volume flow rate was 0.8 mL/min; column temperature 30 ℃; injection volume was 10 μL; electrospray ion source (ESI), negative ion scanning mode, dynamic multi reaction monitoring mode (MRM). The results showed that LC-MS/MS was rapid, sensitive and specific. After ig adenine for 21 days, compared with control group, the kidney of the model group was hypertrophy and pale, the number of renal corpuscles in the tissue section of model group was reduced, the glomerular capsule cavity was enlarged, and there was brown adenine deposition in the renal tubules. Compared with control group, the body weight of CRF rats was significantly reduced from the 10th day of modeling (P < 0.05). After modeling, the kidney weight, 24 h urine volume, serum creatinine and urea nitrogen levels were significantly increased (P < 0.05), and the CRF rat model was successfully established. In CRF rats, area under the plasma concentration-time curve (AUC_0-t) and maximum plasma concentration (C_max) of astragaloside IV were significantly decreased by 28.6% and 21.6%, respectively (P < 0.05). The half-life (t_1/2z) of astragaloside IV and rhein were significantly reduced by 23.5% and 43.7%, respectively (P < 0.05). Conclusion Shenkang Injection exhibited an accelerated clearance in CRF rats, which might shorten effective period.

R969.1

國家自然科學基金資助項目（81302838，81903706）