The present studies were carried out to evaluate the simultaneous one-pot metabolism of opipramol (IS-opi) and analog (IS-noh) by phase I and phase II enzymes present in rat liver microsomes (RLM) as an alternative to separate testing with recombinant enzymes. This approach allows for more time-saving and cost-effective screening of the metabolism of newly discovered drugs. We also considered that the lack of results for phase II, including UGT, often creates problems in correct selection of valuable compounds. Moreover, microsomes data set is richer in the contest and provides medical scientist to determine also the susceptibility of drugs to undergo phase I and then phase II. In the present work, we have shown that IS-noh was metabolized in vitro by phase I enzymes to the oxidation product, which was next transformed with UGTs to glucuronide. The results showed also that the previously known oxidation product of opipramol was changed to previously no reported glucuronidation product by UDP-glucuronosyltransferases. In addition, unlike IS-noh, opipramol did not prove to be the substrate for UGTs. Therefore, tricyclic antidepressants depending on the structure can trigger a different response after contact with UGT enzymes. Some will metabolize directly with UGTs, others only after activation by phase I enzymes.

本研究旨在评估大鼠肝微粒体 (RLM) 中存在的 I 期和 II 期酶对 opipramol (IS-opi) 和类似物 (IS-noh) 的同步一锅代谢，作为单独测试的替代方法重组酶。这种方法允许对新发现药物的代谢进行更节省时间和更具成本效益的筛选。我们还认为，由于缺乏包括 UGT 在内的 II 期结果，通常会在正确选择有价值的化合物方面造成问题。此外，微粒体数据集在比赛中更加丰富，并为医学科学家提供了确定药物经历 I 阶段和 II 阶段的敏感性。在目前的工作中，我们已经证明 IS-noh 在体外被 I 相酶代谢为氧化产物，然后用 UGT 将其转化为葡萄糖醛酸。结果还表明，先前已知的奥匹拉莫氧化产物被 UDP-葡萄糖醛酸基转移酶改变为先前未报道的葡萄糖醛酸化产物。此外，与 IS-noh 不同，opipramol 并未被证明是 UGT 的底物。因此，根据结构的不同，三环类抗抑郁药在与 UGT 酶接触后会触发不同的反应。有些会直接与 UGT 代谢，有些则仅在被 I 相酶激活后才代谢。