PMID- 28428366 OWN - NLM STAT- MEDLINE DCOM- 20180307 LR - 20190125 IS - 1521-009X (Electronic) IS - 0090-9556 (Print) IS - 0090-9556 (Linking) VI - 45 IP - 7 DP - 2017 Jul TI - In Vitro Metabolism of Oprozomib, an Oral Proteasome Inhibitor: Role of Epoxide Hydrolases and Cytochrome P450s. PG - 712-720 LID - 10.1124/dmd.117.075226 [doi] AB - Oprozomib is an oral proteasome inhibitor currently under investigation in patients with hematologic malignancies or solid tumors. Oprozomib elicits potent pharmacological actions by forming a covalent bond with the active site N-terminal threonine of the 20S proteasome. Oprozomib has a short half-life across preclinical 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 P450 (P450) inhibitor 1-aminobenzotriazole resulted in a modest reduction ( approximately 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 clinically significant DDIs with oprozomib. On the other hand, pharmacokinetics of oprozomib is unlikely to be affected by coadministered P450 and sEH inhibitors and/or inducers. CI - Copyright (c) 2017 by The American Society for Pharmacology and Experimental Therapeutics. FAU - Wang, Zhican AU - Wang Z AD - Department of Pharmacokinetics and Drug Metabolism (Zhi.W., Y.F., D.A.R., Zhe.W.), and Clinical Pharmacology Modeling and Simulation (H.W.), Amgen Inc., South San Francisco, California; Drug Metabolism and Pharmacokinetics, Onyx Pharmaceuticals, an Amgen Subsidiary, South San Francisco, California (J.T.); and Department of Entomology and Nematology, and UC Davis Comprehensive Cancer Center, University of California, Davis, Davis, California (C.M., B.D.H.). FAU - Fang, Ying AU - Fang Y AD - Department of Pharmacokinetics and Drug Metabolism (Zhi.W., Y.F., D.A.R., Zhe.W.), and Clinical Pharmacology Modeling and Simulation (H.W.), Amgen Inc., South San Francisco, California; Drug Metabolism and Pharmacokinetics, Onyx Pharmaceuticals, an Amgen Subsidiary, South San Francisco, California (J.T.); and Department of Entomology and Nematology, and UC Davis Comprehensive Cancer Center, University of California, Davis, Davis, California (C.M., B.D.H.). FAU - Teague, Juli AU - Teague J AD - Department of Pharmacokinetics and Drug Metabolism (Zhi.W., Y.F., D.A.R., Zhe.W.), and Clinical Pharmacology Modeling and Simulation (H.W.), Amgen Inc., South San Francisco, California; Drug Metabolism and Pharmacokinetics, Onyx Pharmaceuticals, an Amgen Subsidiary, South San Francisco, California (J.T.); and Department of Entomology and Nematology, and UC Davis Comprehensive Cancer Center, University of California, Davis, Davis, California (C.M., B.D.H.). FAU - Wong, Hansen AU - Wong H AD - Department of Pharmacokinetics and Drug Metabolism (Zhi.W., Y.F., D.A.R., Zhe.W.), and Clinical Pharmacology Modeling and Simulation (H.W.), Amgen Inc., South San Francisco, California; Drug Metabolism and Pharmacokinetics, Onyx Pharmaceuticals, an Amgen Subsidiary, South San Francisco, California (J.T.); and Department of Entomology and Nematology, and UC Davis Comprehensive Cancer Center, University of California, Davis, Davis, California (C.M., B.D.H.). FAU - Morisseau, Christophe AU - Morisseau C AD - Department of Pharmacokinetics and Drug Metabolism (Zhi.W., Y.F., D.A.R., Zhe.W.), and Clinical Pharmacology Modeling and Simulation (H.W.), Amgen Inc., South San Francisco, California; Drug Metabolism and Pharmacokinetics, Onyx Pharmaceuticals, an Amgen Subsidiary, South San Francisco, California (J.T.); and Department of Entomology and Nematology, and UC Davis Comprehensive Cancer Center, University of California, Davis, Davis, California (C.M., B.D.H.). FAU - Hammock, Bruce D AU - Hammock BD AD - Department of Pharmacokinetics and Drug Metabolism (Zhi.W., Y.F., D.A.R., Zhe.W.), and Clinical Pharmacology Modeling and Simulation (H.W.), Amgen Inc., South San Francisco, California; Drug Metabolism and Pharmacokinetics, Onyx Pharmaceuticals, an Amgen Subsidiary, South San Francisco, California (J.T.); and Department of Entomology and Nematology, and UC Davis Comprehensive Cancer Center, University of California, Davis, Davis, California (C.M., B.D.H.). FAU - Rock, Dan A AU - Rock DA AD - Department of Pharmacokinetics and Drug Metabolism (Zhi.W., Y.F., D.A.R., Zhe.W.), and Clinical Pharmacology Modeling and Simulation (H.W.), Amgen Inc., South San Francisco, California; Drug Metabolism and Pharmacokinetics, Onyx Pharmaceuticals, an Amgen Subsidiary, South San Francisco, California (J.T.); and Department of Entomology and Nematology, and UC Davis Comprehensive Cancer Center, University of California, Davis, Davis, California (C.M., B.D.H.). FAU - Wang, Zhengping AU - Wang Z AD - Department of Pharmacokinetics and Drug Metabolism (Zhi.W., Y.F., D.A.R., Zhe.W.), and Clinical Pharmacology Modeling and Simulation (H.W.), Amgen Inc., South San Francisco, California; Drug Metabolism and Pharmacokinetics, Onyx Pharmaceuticals, an Amgen Subsidiary, South San Francisco, California (J.T.); and Department of Entomology and Nematology, and UC Davis Comprehensive Cancer Center, University of California, Davis, Davis, California (C.M., B.D.H.) zwang687@gmail.com. LA - eng GR - P41 RR013461/RR/NCRR NIH HHS/United States GR - P42 ES004699/ES/NIEHS NIH HHS/United States GR - R01 ES002710/ES/NIEHS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20170420 PL - United States TA - Drug Metab Dispos JT - Drug metabolism and disposition: the biological fate of chemicals JID - 9421550 RN - 0 (Proteasome Inhibitors) RN - 0 (Recombinant Proteins) RN - 0 (Triazoles) RN - 016U10PN9N (opromazine) RN - 1614-12-6 (1-aminobenzotriazole) RN - 9035-51-2 (Cytochrome P-450 Enzyme System) RN - EC 3.3.2.- (Epoxide Hydrolases) RN - U42B7VYA4P (Chlorpromazine) SB - IM MH - Administration, Oral MH - Adult MH - Chlorpromazine/*analogs & derivatives/metabolism MH - Cytochrome P-450 Enzyme System/*metabolism MH - Drug Interactions/physiology MH - Epoxide Hydrolases/*metabolism MH - Female MH - Half-Life MH - Hepatocytes/metabolism MH - Humans MH - Male MH - Microsomes, Liver/metabolism MH - Middle Aged MH - Oxidation-Reduction MH - Proteasome Inhibitors/*metabolism MH - Recombinant Proteins/metabolism MH - Triazoles/metabolism MH - Young Adult PMC - PMC5452678 EDAT- 2017/04/22 06:00 MHDA- 2018/03/08 06:00 PMCR- 2018/07/01 CRDT- 2017/04/22 06:00 PHST- 2017/01/25 00:00 [received] PHST- 2017/04/14 00:00 [accepted] PHST- 2017/04/22 06:00 [pubmed] PHST- 2018/03/08 06:00 [medline] PHST- 2017/04/22 06:00 [entrez] PHST- 2018/07/01 00:00 [pmc-release] AID - dmd.117.075226 [pii] AID - DMD_075226 [pii] AID - 10.1124/dmd.117.075226 [doi] PST - ppublish SO - Drug Metab Dispos. 2017 Jul;45(7):712-720. doi: 10.1124/dmd.117.075226. Epub 2017 Apr 20.