目的 建立高效液相色譜-串聯(lián)質(zhì)譜（HPLC-MS/MS）法同時(shí)測(cè)定大鼠血漿中伏立康唑和卡泊芬凈的濃度，并用于伏立康唑和卡泊芬凈單獨(dú)給藥和聯(lián)合給藥后SD大鼠體內(nèi)的藥動(dòng)學(xué)初步研究。方法 伏立康唑、卡泊芬凈分別以氘代伏立康唑和氘代卡泊芬凈為內(nèi)標(biāo)，血漿樣品經(jīng)乙腈提取，以0.1%甲酸-乙腈和0.1%甲酸-水為流動(dòng)相，用Phenomenex SynergiHydro-RP 80A柱進(jìn)行梯度分離，0.5 mL/min體積流量，柱溫為常溫，10 μL進(jìn)樣量，多級(jí)反應(yīng)監(jiān)測(cè)（MRM）ESI正離子模式；12只SD大鼠隨機(jī)分成3組，即伏立康唑（ig，40 mg/kg）組、卡泊芬凈（iv，5 mg/kg）組、伏立康唑（ig，40 mg/kg）與卡泊芬凈（iv 5 mg/kg）聯(lián)合給藥組，分別于給藥后不同時(shí)間點(diǎn)頸靜脈采血進(jìn)行濃度測(cè)定，并計(jì)算藥動(dòng)學(xué)參數(shù)。結(jié)果 伏立康唑在0.5~500.0 ng/mL、卡泊芬凈在4~4 000 ng/mL線性關(guān)系均良好，批內(nèi)精密度（RSD%）和準(zhǔn)確度（RE%）均小于10%，伏立康唑和卡泊芬凈提取回收率均大于90%；SD大鼠單劑量聯(lián)合給予伏立康唑和卡泊芬凈后，伏立康唑消除變快，卡泊芬凈的消除變慢；伏立康唑、卡泊芬凈的C_max、AUC均高于單獨(dú)用藥。結(jié)論 HPLC-MS/MS法的專屬性強(qiáng)、靈敏、準(zhǔn)確、可靠，可用于測(cè)定SD大鼠血漿中伏立康唑和卡泊芬凈的濃度及藥動(dòng)學(xué)研究。伏立康唑延緩了卡泊芬凈在動(dòng)物體內(nèi)的消除速度，卡泊芬凈通過促進(jìn)伏立康唑的吸收，增加了其在動(dòng)物體內(nèi)的血藥濃度，聯(lián)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

廣東省科技計(jì)劃項(xiàng)目（2014A010107018、2017B030314171、2017A070702001）