■为了研究曲马多与代表性酪氨酸激酶抑制剂之间的相互作用,研究药物相互作用的抑制模式。
■建立了肝微粒体催化试验。给Sprague-Dawley大鼠施用曲马多,有或没有选择的酪氨酸激酶抑制剂。制备样品并使用超高效液相色谱-串联质谱(UPLC-MS/MS)进行分析。此外,肝脏,肾,收集小肠,并通过血氧线-伊红(H&E)染色检查形态。同时,制备肝微粒体,并进行一氧化碳差示紫外辐射(UV)分光光度定量。
■在筛选的抑制剂中,克唑替尼在抑制曲马多在大鼠/人类肝微粒体中的代谢方面具有最高效力,遵循非竞争性抑制机制。在体内,当克唑替尼共用药时,曲马多的AUC值较对照组升高。此外,未观察到明显的病理变化,包括细胞形态学,尺寸,安排,多次服用克唑替尼后,随着丙氨酸转氨酶(ALT)和天冬氨酸转氨酶(AST)水平的增加,核形态。同时,发现组合组大鼠肝脏中CYP2D1和CYP3A2的活性以及总细胞色素P450丰度降低。
■克唑替尼能抑制曲马多的代谢。因此,这个食谱应该警惕,以防止不良反应。
UNASSIGNED: To investigate the interaction between tramadol and representative tyrosine kinase inhibitors, and to study the inhibition mode of drug-interaction.
UNASSIGNED: Liver microsomal catalyzing assay was developed. Sprague-Dawley rats were administrated tramadol with or without selected tyrosine kinase inhibitors. Samples were prepared and ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used for analysis. Besides, liver, kidney, and small intestine were collected and morphology was examined by hematoxyline-eosin (H&E) staining. Meanwhile, liver microsomes were prepared and carbon monoxide differential ultraviolet radiation (UV) spectrophotometric quantification was performed.
UNASSIGNED: Among the screened inhibitors,
crizotinib takes the highest potency in suppressing the metabolism of tramadol in rat/human liver microsome, following non-competitive inhibitory mechanism. In vivo, when
crizotinib was co-administered, the AUC value of tramadol increased compared with the control group. Besides, no obvious pathological changes were observed, including cell morphology, size, arrangement, nuclear morphology with the levels of alanine transaminase (ALT) and aspartate transaminase (AST) increased after multiple administration of
crizotinib. Meanwhile, the activities of CYP2D1 and CYP3A2 as well as the total cytochrome P450 abundance were found to be decreased in rat liver of combinational group.
UNASSIGNED: Crizotinib can inhibit the metabolism of tramadol. Therefore, this recipe should be vigilant to prevent adverse reactions.