In vitro metabolism of oprozomib, an oral proteasome inhibitor: role of epoxide hydrolases and cytochrome P450s was written by Wang, Zhican;Fang, Ying;Teague, Juli;Wong, Hansen;Morisseau, Christophe;Hammock, Bruce D.;Rock, Dan A.;Wang, Zhengping. And the article was included in Drug Metabolism & Disposition in 2017.Recommanded Product: 1614-12-6 This article mentions the following:
Oprozomib is an oral proteasome inhibitor currently under investigation in patients with hematol. malignancies or solid tumors. Oprozomib elicits potent pharmacol. actions by forming a covalent bond with the active site N-terminal threonine of the 20S proteasome. Oprozomib has a short half-life across preclin. species and in patients due to systemic clearance via metabolism Potential for drug-drug interactions (DDIs) could alter the exposure of this potent therapeutic; therefore, a thorough investigation of pathways responsible for metabolism is required. In the present study, the major drug-metabolizing enzyme responsible for oprozomib metabolism was identified in vitro. A diol of oprozomib was found to be the predominant metabolite in human hepatocytes, which formed via direct epoxide hydrolysis. Using recombinant epoxide hydrolases (EHs) and selective EH inhibitors in liver microsomes, microsomal EH (mEH) but not soluble EH (sEH) was found to be responsible for oprozomib diol formation. Coincubation with 2-nonylsulfanyl-propionamide, a selective mEH inhibitor, resulted in a significant decrease in oprozomib disappearance (>80%) with concurrent complete blockage of diol formation in human hepatocytes. On the contrary, a selective sEH inhibitor did not affect oprozomib metabolism Pretreatment of hepatocytes with the pan-cytochrome P 450 (P 450) inhibitor 1-aminobenzotriazole resulted in a modest reduction (∼20%) of oprozomib metabolism These findings indicated that mEH plays a predominant role in oprozomib metabolism Further studies may be warranted to determine whether drugs that are mEH inhibitors cause clin. significant DDIs with oprozomib. On the other hand, pharmacokinetics of oprozomib is unlikely to be affected by coadministered P 450 and sEH inhibitors and/or inducers. In the experiment, the researchers used many compounds, for example, 1H-Benzo[d][1,2,3]triazol-1-amine (cas: 1614-12-6Recommanded Product: 1614-12-6).
1H-Benzo[d][1,2,3]triazol-1-amine (cas: 1614-12-6) belongs to triazole derivatives. Triazoles consist of a five-membered ring containing three nitrogen atoms and are biologically active, especially as antifungal, antimicrobial and enzyme inhibitors. Triazole growth retardants such as uniconazole and paclobutrazol have been known to inhibit the biosynthesis of gibberellins by blocking kaurene oxidase, an P450 enzymeRecommanded Product: 1614-12-6
Referemce:
1,2,3-Triazole – Wikipedia,
Triazoles – an overview | ScienceDirect Topics