目的 建立高效液相色谱-串联质谱（HPLC-MS/MS）法同时测定大鼠血浆中伏立康唑和卡泊芬净的浓度，并用于伏立康唑和卡泊芬净单独给药和联合给药后SD大鼠体内的药动学初步研究。方法 伏立康唑、卡泊芬净分别以氘代伏立康唑和氘代卡泊芬净为内标，血浆样品经乙腈提取，以0.1%甲酸-乙腈和0.1%甲酸-水为流动相，用Phenomenex SynergiHydro-RP 80A柱进行梯度分离，0.5 mL/min体积流量，柱温为常温，10 μL进样量，多级反应监测（MRM）ESI正离子模式；12只SD大鼠随机分成3组，即伏立康唑（ig，40 mg/kg）组、卡泊芬净（iv，5 mg/kg）组、伏立康唑（ig，40 mg/kg）与卡泊芬净（iv 5 mg/kg）联合给药组，分别于给药后不同时间点颈静脉采血进行浓度测定，并计算药动学参数。结果 伏立康唑在0.5~500.0 ng/mL、卡泊芬净在4~4 000 ng/mL线性关系均良好，批内精密度（RSD%）和准确度（RE%）均小于10%，伏立康唑和卡泊芬净提取回收率均大于90%；SD大鼠单剂量联合给予伏立康唑和卡泊芬净后，伏立康唑消除变快，卡泊芬净的消除变慢；伏立康唑、卡泊芬净的C_max、AUC均高于单独用药。结论 HPLC-MS/MS法的专属性强、灵敏、准确、可靠，可用于测定SD大鼠血浆中伏立康唑和卡泊芬净的浓度及药动学研究。伏立康唑延缓了卡泊芬净在动物体内的消除速度，卡泊芬净通过促进伏立康唑的吸收，增加了其在动物体内的血药浓度，联用后二者生物利用度均提高。

Objective To determine the concentrations of voriconazole and caspofungin in SD rat plasma by liquid chromatographytandem mass spectrometry (HPLC-MS/MS) and its pharmacokinetics in SD rats after single dose combination treatment with voriconazole and caspofungin. Methods The internal standards of Veconazole and Carpofen were deuterated Vriconazole and caspofungin, respectively. Plasma samples were extracted with acetonitrile, 0.1% formic acid-acetonitrile and 0.1% formic acidwater were used as mobile phase to gradiently separate by Phenomenex Synergi Hydro-RP 80A (30×2.0 mm, 4 μm). with a flow rate of 0.5 mL/min, normal temperature, 10 μL of injection volume, multilevel reaction Monitoring (MRM) ESI positive ion model. 12 mice were randomly devided into three groups:voriconazolehe (ig, 40 mg/kg) group; caspofungin (iv 5 mg/kg); combination group of two drugs (40 mg/kg voriconazolehe and 5 mg/kg caspofungin acetate). Finally, the blood was collected by jugular vein bleeding to measure the the concentrations of voriconazole and caspofungin in SD rat plasma. Results The linear relationship between voriconazole at 0.5 -500.0 ng/mL and caspofungin at 4-4 000 ng/mL was good, and the intra-assay precision (RSD%) and accuracy (RE%) were less than 10%, the recovery of voriconazole and caspofungin extraction were higher than 90%. After single dose of voriconazole and caspofungin, the elimination of voriconazole was faster, and the elimination of caspofungin was slower; the C_max and AUC of voriconazole and caspofungin were higher than those of single dose. Conclusion The HPLC-MS/MS method is specific, sensitive, accurate and reliable. It can be used to determine the concentration and pharmacokinetics of voriconazole and caspofungin in the plasma of SD rats. Voriconazole delayed the elimination rate of caspofungin in animals. Caspofungin increased the blood concentration of voriconazole by promoting the absorption of voriconazole. The bioavailability of both drugs was improved after combination.

R969.1;Q95-33

广东省科技计划项目（2014A010107018、2017B030314171、2017A070702001）