齐墩果酸对拉莫三嗪在大鼠体内药代动力学的影响

Effect of oleanolic acid on pharmacokinetics of lamotrigine in rats

目的通过建立测定拉莫三嗪(LTG)的血药浓度的UHPLC-MS/MS方法,探讨在大鼠体内单次使用和长期使用齐墩果酸对拉莫三嗪的药代动力学参数影响,进而探讨体内齐墩果酸对拉莫三嗪的药代动力学的影响。方法选用雄性SD大鼠,设置对照组、齐墩果酸单次给药组和齐墩果酸长期给药组,每组SD大鼠各8只进行造模,对大鼠血浆中拉莫三嗪的浓度进行检测,通过DAS 3.0计算各组拉莫三嗪的药代动力学参数,绘制药时曲线图,通过SPSS 23.0软件比较各组间拉莫三嗪的药代动力学参数的差异,研究齐墩果酸对拉莫三嗪药代动力学的影响。结果拉莫三嗪在0.05~10μg·mL^(-1)线性关系良好,日间、日内精密度均小于15%,回收率大于95%,稳定性较好。长期给药组的拉莫三嗪AUC_(0-t)为(347.36±181.03)μg·L^(-1)·h,C_(max)为(17.89±9.70)μg·L^(-1);单次给药组的拉莫三嗪AUC_(0-t)为(131.66±41.76)μg·L^(-1)·h,C_(max)为(8.74±3.05)μg·L^(-1);对照组的拉莫三嗪AUC_(0-t)为(91.95±42.07)μg·L^(-1)·h,C_(max)为(6.54±2.99)μg·L^(-1)。长期给药组的拉莫三嗪AUC_(0-t)明显增高,为对照组的3.8倍(P<0.05);C_(max)为对照组的2.7倍(P<0.05),同时清除率降低了70%(P<0.05),表明长期给药齐墩果酸明显抑制了拉莫三嗪在大鼠体内的代谢,提高了拉莫三嗪在体内的暴露量。单次给药组的拉莫三嗪AUC_(0-t)为对照组的1.4倍,C_(max)为对照组的1.3倍,但差异无统计学意义。结论齐墩果酸可抑制大鼠体内拉莫三嗪的代谢。临床上齐墩果酸与拉莫三嗪合用时,需考虑药物浓度变化的影响。

Objective To investigate the effect of oleanolic acid on the pharmacokinetics of lamotrigine(LTG) in rats by establishing a UHPLC-MS/MS method for the determination of lamotrigine in plasma. Methods Male SD rats were divided into control group, oleanolic acid single administration group and oleanolic acid long-term administration group, 8 rats in each group were used to establish the model, the concentration of lamotrigine in rat plasma was detected, the kinetic parameters of lamotrigine in each group were calculated by DAS 3.0, and the drug time curve was drawn. SPSS 23.0 was used to compare the differences of the pharmacokinetic parameters of LTG among the groups and study the effect on the pharma kinetic of lamotrigine afect by oleanolic. Results The linear range of lamotrigine was 0.05-10 μg·mL^(-1), the inter-day and intra-day precision were less than 15%,the recovery was more than 95%,and the stability was good. The AUC_(0-t) of lamotrigine in long-term administration group was( 347. 36 ± 181. 03) μg·L^(-1)·h,Cm ax was( 17. 89 ± 9. 70) μg·L^(-1);AUC_(0-t) in the single dose administration group was( 131. 66 ± 41. 76) μg·L^(-1)·h,Cm ax was( 8. 74 ± 3. 05) μg·L^(-1);AUC_(0-t) in control group was( 91. 95 ± 42. 07) μg·L^(-1)·h,Cm ax was( 6. 54 ± 2. 99) μg·L^(-1). AUC_(0-t) of lamotrigine in the long-term administration group was 3. 8 times higher than that in control group( P < 0. 05),Cm ax was 2. 7 times higher than that in control group( P < 0. 05),and clearence was decreased by 70%( P < 0. 05),indicating that long-term administration of oleanolic acid significantly inhibited the metabolism of lamotrigine in rats and increased the exposure of lamotrigine in vivo. The AUC_(0-t) and Cm ax of lamotrigine in the single dose administration group were 1. 4 and 1. 3 times higher than those in the control group,but there was no significant difference. Conclusion Oleanolic acid can inhibit lamotrigine metabolism in rats. When oleanolic acid is combined with lamotrigine in clinic,the effect of drug concentration should be considered.