Naringenin has an inhibitory effect on rivaroxaban in rats both in vitro and in vivo
Naringenin has an inhibitory effect on rivaroxaban in rats both in vitro and in vivo
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DOI：
10.1002/prp2.782
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发表时间：
2021-05-05
影响因子：
2.6
通讯作者：
Wang S
中科院分区：
文献类型：
--
作者：
Shi H;Zhao F;Chen H;Zhou Q;Geng P;Zhou Y;Wu H;Chong J;Wang F;Dai D;Yang J;Wang S
据报道，食物-药物相互作用对各种口服药物的药代动力学和药效学有一些影响。为了更好地了解柚皮素（多种水果中的一种天然产物）对利伐沙班药代动力学的影响，在Sprague-Dawley（SD）大鼠肝微粒体中研究了柚皮素与利伐沙班之间的体外药物相互作用（DDI）。体内DDI实验选用12只雄性SD大鼠，随机分为实验组和对照组，每组6只。实验组大鼠在经口灌胃给予利伐沙班（10 mg/kg）前，用柚皮素（10 mg/kg/天）预处理2周，而对照组大鼠仅给予利伐沙班（10 mg/kg）一次。体外实验结果表明，柚皮素可降低利伐沙班的代谢清除率，其IC 50值为38.89 μM，对利伐沙班具有混合抑制作用（Ki =54.91 μM，阿基=73.33 μM，a = 0.74）。大鼠体内数据显示，与对照组相比，实验组大鼠的AUC（0- t）值从2406.28 ± 519.69 μg/h/L增加至4005.04 ± 1172.76 μg/h/L，Cmax值从310.23 ± 85.76 μg/L增加至508.71 ± 152.48 μg/L，Vz / F和CLz / F分别由23.03 ± 4.81 L/kg降至16.2 ± 8.42 L/kg和4.26 ± 0.91 L/h/kg降至2.57 ± 0.73 L/h/kg。这些数据表明，柚皮素对利伐沙班在大鼠体内的药代动力学具有抑制作用，表明柚皮素和利伐沙班在临床联合给药时可能发生DDI。在大鼠肝微粒体中，柚皮素以剂量依赖性方式抑制利伐沙班的代谢。柚皮素对大鼠利伐沙班的AUC（0- t）、Cmax值增加，Vz/ F、CLz / F值降低。
Food–drug interactions are reported to have some impacts on the pharmacokinetics and pharmacodynamics of various oral drugs. To better understand the effects of naringenin, one natural product in many fruits, on the pharmacokinetics of rivaroxaban, drug–drug interactions (DDIs) between naringenin and rivaroxaban in vitro were investigated in Sprague–Dawley (SD) rat liver microsomes. For the DDIs in vivo, 12 male SD rats were randomly divided into the experimental group and the control group with six rats in each group. Rats in the experimental group were pre‐treated with naringenin (10 mg/kg/day) for 2 weeks before the administration of rivaroxaban (10 mg/kg) by oral gavage, while the rats in the control group were given rivaroxaban (10 mg/kg) only once. The plasma concentration of rivaroxaban in rats was then measured by UPLC‐MS/MS. In vitro data indicated that naringenin could decrease the metabolic clearance rate of rivaroxaban with the IC50 value of 38.89 μM, and exhibited a mixed inhibition to rivaroxaban (Ki =54.91 μM, aKi =73.33 μM, a = 0.74). In vivo data in rats revealed that as compared with that of the control group, the AUC(0– t ) value of rats in the experimental group was increased from 2406.28 ± 519.69 μg/h/L to 4005.04 ± 1172.76 μg/h/L, the C max value was increased from 310.23 ± 85.76 μg/L to 508.71 ± 152.48 μg/L, and the Vz / F and CLz / F were decreased from 23.03 ± 4.81 L/kg to 16.2 ± 8.42 L/kg, 4.26 ± 0.91 L/h/kg to 2.57 ± 0.73 L/h/kg, respectively. These data indicated that naringenin had an inhibitory effect on the pharmacokinetics of rivaroxaban in rats, suggesting that the DDIs between naringenin and rivaroxaban might occur when they were co‐administered in the clinic. The metabolism of rivaroxaban was inhibited by naringenin in a dose‐dependent manner in rat liver microsomes. Naringenin also exhibited inhibitory effect on rivaroxaban with increased AUC(0– t ), C max values and decreased V z / F, CLz / F values in rat.
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