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首页> 外文期刊>Xenobiotica: the fate of foreign compounds in biological systems >Drug-drug interactions in the metabolism of imidafenacin: role of the human cytochrome P450 enzymes and UDP-glucuronic acid transferases, and potential of imidafenacin to inhibit human cytochrome P450 enzymes.
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Drug-drug interactions in the metabolism of imidafenacin: role of the human cytochrome P450 enzymes and UDP-glucuronic acid transferases, and potential of imidafenacin to inhibit human cytochrome P450 enzymes.

机译：吡虫啉新陈代谢中的药物相互作用：人类细胞色素P450酶和UDP-葡萄糖醛酸转移酶的作用，以及吡虫啉抑制人细胞色素P450酶的潜力。

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摘要

Imidafenacin (IM), 4-(2-methyl-1H-imidazol-1-yl)-2,2-diphenylbutanamide, is a newly synthesized antimuscarinic drug developed for the treatment of overactive bladder. To predict clinically relevant drug interactions in the metabolism of IM, the paper investigated: (1) the major enzymes responsible for the metabolism of IM, (2) the effects of concomitant drugs on the inhibition of metabolism of IM, and (3) the effects of IM and its metabolites on the inhibition of human cytochrome P450 (CYP). The elimination of IM and production of oxidative metabolites were mainly catalysed by recombinant CYP3A4, and the elimination of IM by human liver microsomes (HLM) was markedly inhibited by co-incubation with ketoconazole. The production of the N-glucuronide metabolite was only catalysed by recombinant UGT1A4. Clinically established CYP3A4 inhibitors including itraconazole, ketoconazole, erythromycin and clarithromycin inhibited the elimination of IM in HLM. IM and its major metabolites did not affect the activities of CYP enzymes in vitro. The results suggest that the major enzymes responsible for the metabolism of IM are CYP3A4 and UGT1A4, and oxidative metabolism of IM is reduced by concomitant administration of CYP3A4 inhibitors. In contrast, IM and its metabolites have no inhibitory effect on the CYP-mediated metabolism of concomitant drugs.
机译：吡虫啉（IM）4-（2-甲基-1H-咪唑-1-基）-2,2-二苯基丁酰胺是一种新合成的抗毒蕈碱药物，用于治疗膀胱过度活动症。为了预测IM代谢中与临床相关的药物相互作用，本文研究了：（1）负责IM代谢的主要酶，（2）伴随药物对IM代谢的抑制作用，以及（3）及其代谢物对人细胞色素P450（CYP）的抑制作用IM的消除和氧化代谢产物的产生主要由重组CYP3A4催化，而人肝微粒体（HLM）与酮康唑的共孵育显着抑制了IM的消除。 N-葡糖醛酸苷代谢产物的产生仅由重组UGT1A4催化。临床确定的CYP3A4抑制剂，包括伊曲康唑，酮康唑，红霉素和克拉霉素，抑制HLM中IM的消除。 IM及其主要代谢产物在体外不影响CYP酶的活性。结果表明，负责IM代谢的主要酶是CYP3A4和UGT1A4，同时服用CYP3A4抑制剂可降低IM的氧化代谢。相反，IM及其代谢物对CYP介导的伴随药物的代谢没有抑制作用。

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