阿布西替尼被批准用于治疗中度至重度特应性皮炎,主要通过细胞色素P450(CYP450)酶消除。两种常用的抗抑郁药,阿米替林和氟西汀,可以抑制CYP2C19和CYP3A4的活性。在这项研究中,我们开发了一种新的快速超高效液相色谱串联质谱(UPLC-MS/MS)方法,用于定量分析abrocitinib的血浆浓度,并进一步研究了阿米替林或氟西汀对abrocitinib在大鼠体内药代动力学的影响。选择性,线性度recovery,准确度,精度,根据美国食品和药物管理局(FDA)和欧洲药品管理局(EMA)指南,UPLC-MS/MS测定的基质效应和稳定性令人满意。我们的结果表明,当与阿米替林和氟西汀共同给药时,abrocitinib的CLz/F分别降低了44.4%和33.3%,分别,而abrocitinib的AUC(0-t)分别增加了77.7%和49.4%,分别。说明阿米替林和氟西汀均能显著提高大鼠血浆阿莫替尼浓度。因此,在正在进行的临床实践中,当abrocitinib与阿米替林或氟西汀联合使用时,可能需要调整abrocitinib的剂量。
Abrocitinib is approved to treat moderate-to-severe atopic dermatitis and eliminated mainly through cytochrome P450 (CYP450) enzyme. Two commonly used antidepressants,
amitriptyline and fluoxetine, could inhibit the activities of CYP2C19 and CYP3A4. In this study, we developed a new and quick ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for quantitatively analyzing the plasma concentration of abrocitinib, and further investigated the effects of
amitriptyline or fluoxetine on the pharmacokinetics of abrocitinib in rats. The selectivity, linearity, recovery, accuracy, precision, matrix effect and stability of UPLC-MS/MS assay were satisfied according to the United States Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidelines. Our result showed that when co-administered with
amitriptyline and fluoxetine, the CLz/F of abrocitinib was reduced by 44.4 % and 33.3 %, respectively, while the AUC(0-t) of abrocitinib was increased by 77.7 % and 49.4 %, respectively. It indicated that
amitriptyline and fluoxetine could significantly increase the plasma concentration of abrocitinib in rats. Thus, dose adjustment of abrocitinib may be required when it is combined with
amitriptyline or fluoxetine in ongoing clinical practice.