| ORIGINAL ARTICLES |
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Metabolism characterization and toxicity of N-hydap, a marine candidate drug for lung cancer therapy by LC-MS method |
| Jindi Lu1, Weimin Liang1, Yiwei Hu2, Xi Zhang1, Ping Yu1, Meiqun Cai1, Danni Xie1, Qiong Zhou1, Xuefeng Zhou2, Yonghong Liu2, Junfeng Wang2, Jiayin Guo1, Lan Tang1 |
1. NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, Southern Medical University Hospital of Integrated Traditional Chinese and Western Medicine, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China;
2. CAS Key Laboratory of Tropical Marine Bio-Resources and Ecology/Guangdong Key Laboratory of Marine Materia Medica, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou 510301, China |
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Abstract N-Hydroxyapiosporamide (N-hydap), a marine product derived from a sponge-associated fungus, has shown promising inhibitory effects on small cell lung cancer (SCLC). However, there is limited understanding of its metabolic pathways and characteristics. This study explored the in vitro metabolic profiles of N-hydap in human recombinant cytochrome P450s (CYPs) and UDP-glucuronosyltransferases (UGTs), as well as human/rat/mice microsomes, and also the pharmacokinetic properties by HPLC-MS/MS. Additionally, the cocktail probe method was used to investigate the potential to create drug-drug interactions (DDIs). N-Hydap was metabolically unstable in various microsomes after 1 h, with about 50% and 70% of it being eliminated by CYPs and UGTs, respectively. UGT1A3 was the main enzyme involved in glucuronidation (over 80%), making glucuronide the primary metabolite. Despite low bioavailability (0.024%), N-hydap exhibited a higher distribution in the lungs (26.26%), accounting for its efficacy against SCLC. Administering N-hydap to mice at normal doses via gavage did not result in significant toxicity. Furthermore, N-hydap was found to affect the catalytic activity of drug metabolic enzymes (DMEs), particularly increasing the activity of UGT1A3, suggesting potential for DDIs. Understanding the metabolic pathways and properties of N-hydap should improve our knowledge of its drug efficacy, toxicity, and potential for DDIs.
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| Keywords
N-Hydap
Metabolism
Pharmacokinetics
DMEs
Toxicity
DDIs
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| Fund:This work was supported by the National Natural Science Foundation of China (Nos. 82274002, 42376124), Marine Economy Development Project of Guangdong Province (GDNRC[2021]52), Hainan Provincial Natural Science Foundation of China (823CXTD393), Key-Area Research and Development Program of Guangdong Province (2023B1111050008) |
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Corresponding Authors:
Junfeng Wang,E-mail:wangjunfeng@scsio.ac.cn;Jiayin Guo,E-mail:g1227@smu.edu.cn;Lan Tang,E-mail:tl405@smu.edu.cn
E-mail: wangjunfeng@scsio.ac.cn;g1227@smu.edu.cn;tl405@smu.edu.cn
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Issue Date: 01 August 2024
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