Inhibitory effects of fluoxetine and duloxetine on the pharmacokinetics of metoprolol in vivo and in vitro
Inhibitory effects of fluoxetine and duloxetine on the pharmacokinetics of metoprolol in vivo and in vitro
复制标题
DOI：
10.1111/fcp.12795
复制
发表时间：
2022-05
影响因子：
2.9
通讯作者：
Tao Xu;Nan-yong Gao;Ying‐hui Li;Ru Wang;Bingbing Chen;G. Hu;Xiaodan Zhang
中科院分区：
文献类型：
--
作者：
Tao Xu;Nan-yong Gao;Ying‐hui Li;Ru Wang;Bingbing Chen;G. Hu;Xiaodan Zhang
抑郁症在患有心血管疾病的人中很常见。因此，抗抑郁药和心血管药物的联合使用非常普遍，这增加了药物相互作用的可能性。同时比较度洛西汀和氟西汀对美托洛尔代谢的影响，为临床用药安全提供循证指导。将SD大鼠随机分为3组：A组(单纯美托洛尔10.3 mg/kg)、B组(10.3 mg/kg美托洛尔+6.2 mg/kg氟西汀)、C组(10.3 mg/kg美托洛尔+6.2 mg/kg度洛西汀)。采集尾静脉血，进行超高效液相色谱-串联质谱仪(UPLC-MS/MS)检测。此外，通过将肝微粒体和CYP2D6.1与美托洛尔孵育来评价氟西汀和度洛西汀的体外抑制作用。体内试验中，氟西汀或度洛西汀显著增加美托洛尔的AUC0−𝑡和AUC0−∞(P<0.0 5)。比较了氟西汀和度洛西汀的血药浓度差异，其AUC0−𝑡和AUC0−∞有显著差异(P<0.0 5)。在体外，氟西汀和度洛西汀通过细胞色素P450的混合竞争机制抑制美托洛尔的代谢。氟西汀和度洛西汀的IC50值分别为12.86和2.51μM。氟西汀和度洛西汀分别抑制美托洛尔在重组人细胞色素P450 2D6.1中的代谢率为19.62%和17.14%。与氟西汀相比，度洛西汀在体外对美托洛尔代谢有更明显的抑制作用，但在体内对美托洛尔代谢的抑制作用不同。
Depression is common among people with cardiovascular diseases. Therefore, the combined use of antidepressants and cardiovascular drugs is very common, which increases the possibility of drug interaction. Simultaneously compare the effects of duloxetine and fluoxetine on metoprolol metabolism, and provide evidence‐based guidance for medication safety. Sprague–Dawley rats were randomly divided into three groups: group A (10.3 mg/kg metoprolol alone), group B (10.3 mg/kg metoprolol + 6.2 mg/kg fluoxetine), and group C (10.3 mg/kg metoprolol + 6.2 mg/kg duloxetine). Tail vein blood was collected and subjected to the ultra‐performance liquid chromatography–tandem mass spectrometry (UPLC‐MS/MS) detection. Moreover, in vitro inhibition of fluoxetine and duloxetine were assessed by incubating liver microsomes and CYP2D6.1 with metoprolol. In in vivo study, the administration of fluoxetine or duloxetine significantly increased the AUC(0−𝑡) and AUC(0−∞) of metoprolol (P < 0.05). Differences between fluoxetine and duloxetine in plasma concentration were also investigated, and their pharmacokinetic parameters such as AUC(0−𝑡) and AUC(0−∞) were significantly distinct (P < 0.05). In vitro, fluoxetine and duloxetine inhibited the metabolism of metoprolol via mixed competitive mechanism of cytochrome P450. IC50 values of fluoxetine and duloxetine were 12.86 and 2.51 μM, respectively. Moreover, the metabolism rate of metoprolol was inhibited to 19.62% and 17.14% in recombinant human CYP2D6.1 by fluoxetine and duloxetine, respectively. Duloxetine showed a more significant inhibitory potential compared to fluoxetine in vitro, but the main pharmacokinetic parameters of fluoxetine and duloxetine revealed differences in inhibiting metoprolol metabolism in vivo.