<i>In vivo</i> evaluation of intestinal human CYP3A inhibition by macrolide antibiotics in CYP3A-humanised mice
<i>In vivo</i> evaluation of intestinal human CYP3A inhibition by macrolide antibiotics in CYP3A-humanised mice
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<i>体内评估大环内酯类抗生素对 CYP3A 人源化小鼠肠道人 CYP3A 的抑制作用
DOI：
10.1080/00498254.2021.1921314
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发表时间：
2021
期刊：
影响因子：
1.8
通讯作者：
Kobayashi Kaoru
中科院分区：
文献类型：
--
作者：
Minegishi Genki;Kazuki Yasuhiro;Nitta Shin-Ichiro;Miyajima Atsushi;Akita Hidetaka;Kobayashi Kaoru
肠道细胞色素P450 3A（CYP 3A）是口服CYP 3A底物生物利用度的决定因素，通过CYP 3A的代谢预测药物相互作用具有重要意义。然而，大环内酯类抗生素对CYP 3A介导的代谢的抑制作用在人类和啮齿类动物中并不完全相同。我们研究了大环内酯类抗生素克拉霉素和红霉素对CYP 3A底物三唑仑体外和体内代谢的影响，在CYP 3A中-通过使用携带人CYP 3A基因的小鼠人工染色体载体产生人源化小鼠。口服三唑仑后4-羟基三唑仑与三唑仑的血浆浓度-时间曲线下面积比通过多次给予大环内酯类抗生素显著降低。多次给药可显著降低CYP 3A人源化小鼠门静脉血中α-羟基三唑仑和4-羟基三唑仑与三唑仑的血药浓度比值，提示大环内酯类抗生素可抑制CYP 3A人源化小鼠肠道CYP 3A活性。CYP 3A人源化小鼠门静脉血中三唑仑及其代谢产物的血浆浓度可用于直接评价肠道CYP 3A介导的药物相互作用。
It is important to predict drug-drug interactionsviainhibition of intestinal cytochrome P450 3A (CYP3A) which is a determinant of bioavailability of orally administered CYP3A substrates. However, inhibitory effects of macrolide antibiotics on CYP3A-mediated metabolism are not entirely identical between humans and rodents.We investigated the effects of macrolide antibiotics, clarithromycin and erythromycin, onin vitroandin vivometabolism of triazolam, a CYP3A substrate, in CYP3A-humanised mice generated by using a mouse artificial chromosome vector carrying a humanCYP3Agene.Metabolic activities of triazolam were inhibited by macrolide antibiotics in liver and intestine microsomes of CYP3A-humanised mice.The area under the plasma concentration-time curve ratios of 4-hydroxytriazolam to triazolam after oral dosing of triazolam were significantly decreased by multiple administration of macrolide antibiotics. The plasma concentrations ratios of α-hydroxytriazolam and 4-hydroxytriazolam to triazolam in portal blood were significantly decreased by multiple administration of clarithromycin in CYP3A-humanised mice.These results suggest that intestinal CYP3A activity was inhibited by macrolide antibiotics in CYP3A-humanised micein vitroandin vivo. The plasma concentrations of triazolam and its metabolites in the portal blood of CYP3A-humanised mice would be useful for direct evaluation of intestinal CYP3A-mediated drug-drug interactions.