少腹逐瘀汤对布洛芬在大鼠体内药动学及代谢产物的影响

Effect of Shaofu Zhuyu Decoction on in vivo pharmacokinetics and metabolites of Ibuprofen in rats

目的揭示少腹逐瘀汤(SZD)对布洛芬在大鼠体内药动学特征及代谢产物的影响。方法采用HPLC-DAD法定量分析SZD与布洛芬合用后布洛芬药动学参数的变化;采用UHPLC-QTOF-MS联用方法,利用碰撞能量梯度(MSE)和质量亏损过滤(MDF)技术,对SZD与布洛芬合用后布洛芬在血浆、尿液、粪便中的代谢产物变化进行研究。结果单独给予布洛芬其在大鼠体内吸收较快,0.5 h达峰,与不同剂量SZD合用后,tmax均延长(P<0.01),Cmax均为下降趋势,但与布洛芬组比较无统计学差异;布洛芬与临床等效量的SZD合用后,AUC显著增高(P<0.05),提示其生物利用度提高,表观清除率降低;与5倍临床剂量的SZD合用后,t1/2z显著降低(P<0.05)。服药2 h后,布洛芬与不同剂量SZD合用后其血药浓度下降均较布洛芬组缓慢。布洛芬单用时其代谢产物主要为2′-羟基布洛芬、2′-羟基布洛芬-葡萄糖醛酸苷、2′-羧基布洛芬和布洛芬-葡萄糖醛酸苷;与SZD合用后,在血浆、尿液、粪便中共发现17个布洛芬的代谢物,其中粪便中存在羟基化产物、降解产物、乙酰化产物、羟基硫酸化产物等;血浆中存在去甲基化产物、羟基化产物、乙酰化产物以及硫酸酯化产物等;尿液中代谢产物除半胱氨酸共价结合物外与布洛芬单用时一致。结论布洛芬与SZD合用后,其在大鼠体内的药动学过程发生变化,且该变化与SZD的剂量存在一定关系,为二者临床联合用药及进一步揭示其药效变化与机制提供了一定参考。

Objective To explore the effect of Shaofu Zhuyu Decoction （SZD） on in vivo pharmacokinefic characteristics and metabolites of Ibuprofen in rats. Methods HPLC-DAD method was established to quantitatively analyze the pharmacokinetic parameters of Ibuprofen combined with SZD. UHPLC-QTOF-MS, MSE, and. mass defect filtering （MDF） were used to investigate the metabolite changes of Ibuprofen in plasma, feces, and urine in rats after ig administration of Ibuprofen combined with SZD. Results The in vivo absorption of single Ibuprofen in rats was quick, which could reach the peak in 0.5 h. After combined with SZD at different concentration, tmax was prolonging （P 〈 0.01） and Cmax was decreasing but no statistic significance was found compared with the Ibuprofen group. When Ibuprofen was used with SZD at the clinical equivalent amount, AUC values were significantly increased （P 〈 0.05）, which showed that bioavailability was increased and the apparent clearance was decreased. When Ibuprofen was used with SZD at five-fold clinical equivalent amount, the tmz of Ibuprofen was decreased significantly （P 〈 0.05）. The decreases of blood-drug concentration after the administration for 2 h in Ibuprofen or Ibuprofen with SZD groups were slower than those in SZD single group. These indicated that the pharmacokinetic characteristics of Ibuprofen were different from those in Ibuprofen with SZD groups, which were dependent on the dosages of SZD. The metabolites of Ibuprofen used signally were 2＇-hydroxy-Ibuprofen, 2＇- hydroxy-Ibuprofen-glucuronide, 2＇-carboxy-Ibuprofen, and Ibuprofen-glucuronide. Total 17 metabolites of Ibuprofen were identified from plasma, urine, and feces after combined with SZD. Hydroxylation, degradation, acetylation, and hydroxy-sulfate products were identified in rat feces, methylation, hydroxylation, acetylation, and sulfation products were identified in rat plasma. There was no significant difference of metabolites in urine except cysteine covalent conjugation. Conclusion The results provide the basis for the clinical use of lbuprofen combined with SZD to illustrate the pharmacodynamic changes and mechanism.