Metabolism characterization and toxicity of N-hydap, a marine candidate drug for lung cancer therapy by LC-MS method

doi:10.1007/s13659-024-00455-x

Natural Products and Bioprospecting ›› 2024, Vol. 14 ›› Issue (4): 33-33.DOI: 10.1007/s13659-024-00455-x

• ORIGINAL ARTICLES • Previous Articles

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

Received:2024-01-24 Online:2024-08-01
Contact: Junfeng Wang,E-mail:wangjunfeng@scsio.ac.cn;Jiayin Guo,E-mail:g1227@smu.edu.cn;Lan Tang,E-mail:tl405@smu.edu.cn
Supported by:
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)

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

通讯作者: Junfeng Wang,E-mail:wangjunfeng@scsio.ac.cn;Jiayin Guo,E-mail:g1227@smu.edu.cn;Lan Tang,E-mail:tl405@smu.edu.cn
基金资助:
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)

Abstract

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.

Key words: N-Hydap, Metabolism, Pharmacokinetics, DMEs, Toxicity, DDIs

摘要： 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.

关键词: N-Hydap, Metabolism, Pharmacokinetics, DMEs, Toxicity, DDIs

Jindi Lu, Weimin Liang, Yiwei Hu, Xi Zhang, Ping Yu, Meiqun Cai, Danni Xie, Qiong Zhou, Xuefeng Zhou, Yonghong Liu, Junfeng Wang, Jiayin Guo, Lan Tang. Metabolism characterization and toxicity of N-hydap, a marine candidate drug for lung cancer therapy by LC-MS method[J]. Natural Products and Bioprospecting, 2024, 14(4): 33-33.

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Metabolism characterization and toxicity of N-hydap, a marine candidate drug for lung cancer therapy by LC-MS method

Metabolism characterization and toxicity of N-hydap, a marine candidate drug for lung cancer therapy by LC-MS method

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