Abstract

1. It is important to predict drug-drug interactions via inhibition 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.

2. We investigated the effects of macrolide antibiotics, clarithromycin and erythromycin, on in vitro and in vivo metabolism of triazolam, a CYP3A substrate, in CYP3A-humanised mice generated by using a mouse artificial chromosome vector carrying a human CYP3A gene.

3. Metabolic activities of triazolam were inhibited by macrolide antibiotics in liver and intestine microsomes of CYP3A-humanised mice.

4. 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.

5. These results suggest that intestinal CYP3A activity was inhibited by macrolide antibiotics in CYP3A-humanised mice in vitro and in 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.

摘要

1. 重要的是通过抑制肠道细胞色素 P450 3A (CYP3A)来预测药物相互作用， CYP3A 是口服 CYP3A 底物生物利用度的决定因素。然而，大环内酯类抗生素对 CYP3A 介导的代谢的抑制作用在人和啮齿动物之间并不完全相同。

2. 我们研究了大环内酯类抗生素、克拉霉素和红霉素对三唑仑（一种 CYP3A 底物）的体外和体内代谢的影响，在使用携带人CYP3A基因的小鼠人工染色体载体生成的 CYP3A 人源化小鼠中。

3. 三唑仑的代谢活性在 CYP3A 人源化小鼠的肝脏和肠道微粒体中被大环内酯类抗生素抑制。

4. 多次给予大环内酯类抗生素后，口服三唑仑后 4-羟基三唑仑与三唑仑的血浆浓度-时间曲线下面积比值显着降低。在 CYP3A 人源化小鼠中多次施用克拉霉素后，门静脉血中 α-羟基三唑仑和 4-羟基三唑仑与三唑仑的血浆浓度比显着降低。

5. 这些结果表明，在体外和体内CYP3A 人源化小鼠中，大环内酯类抗生素可抑制肠道 CYP3A 活性。CYP3A 人源化小鼠门静脉血中三唑仑及其代谢物的血浆浓度可用于直接评估肠道 CYP3A 介导的药物相互作用。