Cytochrome P450-Mediated Metabolism and CYP Inhibition for the Synthetic Peroxide Antimalarial OZ439
文献类型：期刊论文
| 作者 | Shackleford, David M.2; Chiu, Francis C. K.2; Katneni, Kasiram2; Blundell, Scott2,3; McLaren, Jenna2,4; Wang, Xiaofang5; Zhou, Lin5; Sriraghavan, Kamaraj5; Alker, Andre M.6; Hunziker, Daniel6 |
| 刊名 | ACS INFECTIOUS DISEASES
 |
| 出版日期 | 2021-07-09 |
| 卷号 | 7期号:7页码:1885-1893 |
| 关键词 | OZ439 (artefenomel) malaria metabolite identification cytochrome P450 metabolism cytochrome P450 inhibition time-dependent inhibition |
| ISSN号 | 2373-8227 |
| DOI | 10.1021/acsinfecdis.1c00225 |
| 通讯作者 | Charman, Susan A.(susan.charman@monash.edu) |
| 英文摘要 | OZ439 is a potent synthetic ozonide evaluated for the treatment of uncomplicated malaria. The metabolite profile of OZ439 was characterized in vitro using human liver microsomes combined with LC/MS-MS, chemical derivatization, and metabolite synthesis. The primary biotransformations were monohydroxylation at the three distal carbon atoms of the spiroadamantane substructure, with minor contributions from N-oxidation of the morpholine nitrogen and deethylation cleavage of the morpholine ring. Secondary transformations resulted in the formation of dihydroxylation metabolites and metabolites containing both monohydroxylation and morpholine N-oxidation. With the exception of two minor metabolites, none of the other metabolites had appreciable antimalarial activity. Reaction phenotyping indicated that CYP3A4 is the enzyme responsible for the metabolism of OZ439, and it was found to inhibit CYP3A via both direct and mechanism-based inhibition. Elucidation of the metabolic pathways and kinetics will assist with efforts to predict potential metabolic drug-drug interactions and support physiologically based pharmacokinetic (PBPK) modeling. |
| WOS关键词 | PLASMODIUM-FALCIPARUM MALARIA ; MECHANISM-BASED INACTIVATION ; DRUG DEVELOPMENT ; IN-VITRO ; ARTEROLANE ; DIHYDROARTEMISININ ; PHARMACOKINETICS ; MULTICENTER ; ARTEFENOMEL ; TRIOXOLANE |
| 资助项目 | Medicines for Malaria Venture ; Nebraska Research Initiative (NRI) ; Therapeutic Innovation Australia (TIA) ; Australian Government through the National Collaborative Research Infrastructure Strategy (NCRIS) program |
| WOS研究方向 | Pharmacology & Pharmacy ; Infectious Diseases |
| 语种 | 英语 |
| WOS记录号 | WOS:000672742100004 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/298274]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Charman, Susan A. |
| 作者单位 | 1.Swiss Trop & Publ Hlth Inst, CH-4002 Basel, Switzerland 2.Monash Univ, Ctr Drug Candidate Optimisat, Monash Inst Pharmaceut Sci, Parkville Campus, Parkville, Vic 3052, Australia 3.Monash Univ, Level 2,Bldg 75,15 Innovat Walk, Clayton, Vic 3800, Australia 4.Monash Univ, Sch Publ Hlth & Prevent Med, Level 4,553 St Kilda Rd, Melbourne, Vic 3004, Australia 5.Univ Nebraska Med Ctr, Coll Pharm, Omaha, NE 68198 USA 6.F Hoffmann La Roche Ltd, Roche Pharmaceut Res & Early Dev, Roche Innovat Ctr Basel, CH-4070 Basel, Switzerland 7.Univ Basel, CH-4003 Basel, Switzerland 8.Chinese Acad Sci, Shanghai Inst Mat Med, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 9.Med Malaria Venture, CH-1215 Geneva 15, Switzerland |
| 推荐引用方式 GB/T 7714 | Shackleford, David M.,Chiu, Francis C. K.,Katneni, Kasiram,et al. Cytochrome P450-Mediated Metabolism and CYP Inhibition for the Synthetic Peroxide Antimalarial OZ439[J]. ACS INFECTIOUS DISEASES,2021,7(7):1885-1893. |
| APA | Shackleford, David M..,Chiu, Francis C. K..,Katneni, Kasiram.,Blundell, Scott.,McLaren, Jenna.,...&Charman, Susan A..(2021).Cytochrome P450-Mediated Metabolism and CYP Inhibition for the Synthetic Peroxide Antimalarial OZ439.ACS INFECTIOUS DISEASES,7(7),1885-1893. |
| MLA | Shackleford, David M.,et al."Cytochrome P450-Mediated Metabolism and CYP Inhibition for the Synthetic Peroxide Antimalarial OZ439".ACS INFECTIOUS DISEASES 7.7(2021):1885-1893. |
入库方式： OAI收割
来源：上海药物研究所
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