联用丹参对甲氨蝶呤灌胃大鼠体内药物动力学的影响

Influence of Radix Salviae Miltiorrhizae on Methotrexate Pharmacokinetics in Rats

目的比较甲氨蝶呤（MTX）单用与联用丹参时大鼠体内药物动力学参数，探讨丹参对甲氨蝶呤药物动力学以及药效可能的影响。方法选用SD大鼠分别灌胃MTX （剂量为7 mg/kg）或MTX加丹参水煎剂（剂量为3.085 g/kg），于不同时间点眼眶静脉丛采血，采用高氯酸沉淀蛋白法处理血样，高效液相色谱法分析： Diamonsil C18（2）色谱柱；甲醇—体积分数0.1%甲酸水梯度洗脱；流速1 mL/min；柱温27℃；检测波长302 nm；进样量10μL。采用非隔室模型估算药物动力学参数。结果MTX在0.0976～12.5 mg/L线性关系良好（r=0.9985）；定量下限0.0976 mg/L；提取回收率77.5%～86.6%。与MTX组比较，联合用药组MTX达峰时间提前，清除延迟。其中药—时曲线下面积（0-t）[AUC（0-t）]增加0.609倍，药—时曲线下面积（0-∞）[AUC（0-∞）]增加0.786倍。结论丹参水煎液能够促进MTX吸收，延缓其消除，提高其生物利用度。

Objective To compare the pharmacokinetics difference of methotrexate （ MTX） alone or MTX combined with the decoction of Radix Salviae Miltiorrhizae （ RSM） in rats, and to investigate the possible impact of RSM on the efficacy and pharmacokinetics of MTX after oral administration. Methods Sprague-Dawley rats were given MTX （7 mg/kg） alone or MTX together with RSM （3.085 g/kg） respectively. At different time points, blood was sampled from orbital venous plexus and then was precipitated by perchloric acid. The serum concentration of MTX was determined by using high performance liquid chromatography （ HPLC） method. Chromatographic separation was achieved on a reversed-phase Diamonsil C18 （2） column with the mobile phase of methanol-formic acid water solution （formic acid in volume fraction of 0.1%） in gradient elution. The column temperature was 27 ℃, flow rate was 1 mL/min, detection wavelength was 302 nm, and the injection volume was 10 μL. The results were analyzed by pharmacokinetic software DAS （ 2.1.1） by non-compartment model. Results The linearity of the calibration curve for MTX was good in the range of 0.097 6 ~ 12.5 mg/L, the detection limit was 0.097 6 mg/L and the recovery was in the range of 77.5% ~ 86.6%. Compared with MTX group, the peak-arriving time of MTX-RSM group was advanced, and the clearance of MTX was delayed. Area under concentration-time curve at 0-t （AUC（0-t）） was increased by 0.609 times, and AUC（0-∞） was increased by 0.786 times. Conclusion The decoction of RSM exerts an effect on promoting the absorption of MTX, delaying the clearance of MTX and enhancing the bioavailability of MTX in vivo.