Pharmacometabolomic prediction of individual differences of gastrointestinal toxicity complicating myelosuppression in rats induced by irinotecan
Pharmacometabolomics has been already successfully used in toxicity prediction for one specific adverse effect. However in clinical practice, two or more different toxicities are always accompanied with each other, which puts forward new challenges for pharmacometabolomics. Gastrointestinal toxicity...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2019-01-01
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| Series: | Acta Pharmaceutica Sinica B |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211383518304453 |
| _version_ | 1818016464751296512 |
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| author | Yiqiao Gao Wei Li Jiaqing Chen Xu Wang Yingtong Lv Yin Huang Zunjian Zhang Fengguo Xu |
| author_facet | Yiqiao Gao Wei Li Jiaqing Chen Xu Wang Yingtong Lv Yin Huang Zunjian Zhang Fengguo Xu |
| author_sort | Yiqiao Gao |
| collection | DOAJ |
| description | Pharmacometabolomics has been already successfully used in toxicity prediction for one specific adverse effect. However in clinical practice, two or more different toxicities are always accompanied with each other, which puts forward new challenges for pharmacometabolomics. Gastrointestinal toxicity and myelosuppression are two major adverse effects induced by Irinotecan (CPT-11), and often show large individual differences. In the current study, a pharmacometabolomic study was performed to screen the exclusive biomarkers in predose serums which could predict late-onset diarrhea and myelosuppression of CPT-11 simultaneously. The severity and sensitivity differences in gastrointestinal toxicity and myelosuppression were judged by delayed-onset diarrhea symptoms, histopathology examination, relative cytokines and blood cell counts. Mass spectrometry-based non-targeted and targeted metabolomics were conducted in sequence to dissect metabolite signatures in predose serums. Eventually, two groups of metabolites were screened out as predictors for individual differences in late-onset diarrhea and myelosuppression using binary logistic regression, respectively. This result was compared with existing predictors and validated by another independent external validation set. Our study indicates the prediction of toxicity could be possible upon predose metabolic profile. Pharmacometabolomics can be a potentially useful tool for complicating toxicity prediction. Our findings also provide a new insight into CPT-11 precision medicine. KEY WORDS: Irinotecan, Individual differences, Complicating toxicity, Prediction, Metabolomics, Gastrointestinal toxicity, Biomarkers, Diarrhea |
| first_indexed | 2024-04-14T07:12:45Z |
| format | Article |
| id | doaj.art-87ce0a91343942bfa2b63f7c87738087 |
| institution | Directory Open Access Journal |
| issn | 2211-3835 |
| language | English |
| last_indexed | 2024-04-14T07:12:45Z |
| publishDate | 2019-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Acta Pharmaceutica Sinica B |
| spelling | doaj.art-87ce0a91343942bfa2b63f7c877380872022-12-22T02:06:23ZengElsevierActa Pharmaceutica Sinica B2211-38352019-01-0191157166Pharmacometabolomic prediction of individual differences of gastrointestinal toxicity complicating myelosuppression in rats induced by irinotecanYiqiao Gao0Wei Li1Jiaqing Chen2Xu Wang3Yingtong Lv4Yin Huang5Zunjian Zhang6Fengguo Xu7Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing 210009, China; Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, ChinaKey Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing 210009, China; Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, ChinaKey Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing 210009, China; Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, ChinaKey Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing 210009, China; Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, ChinaKey Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing 210009, China; Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, ChinaKey Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing 210009, China; Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, ChinaKey Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing 210009, China; Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China; Corresponding author at: Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing 210009, China. Tel./fax: +86 25 83271454.Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing 210009, China; Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China; Corresponding author at: Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing 210009, China. Tel./fax: +86 25 83271021.Pharmacometabolomics has been already successfully used in toxicity prediction for one specific adverse effect. However in clinical practice, two or more different toxicities are always accompanied with each other, which puts forward new challenges for pharmacometabolomics. Gastrointestinal toxicity and myelosuppression are two major adverse effects induced by Irinotecan (CPT-11), and often show large individual differences. In the current study, a pharmacometabolomic study was performed to screen the exclusive biomarkers in predose serums which could predict late-onset diarrhea and myelosuppression of CPT-11 simultaneously. The severity and sensitivity differences in gastrointestinal toxicity and myelosuppression were judged by delayed-onset diarrhea symptoms, histopathology examination, relative cytokines and blood cell counts. Mass spectrometry-based non-targeted and targeted metabolomics were conducted in sequence to dissect metabolite signatures in predose serums. Eventually, two groups of metabolites were screened out as predictors for individual differences in late-onset diarrhea and myelosuppression using binary logistic regression, respectively. This result was compared with existing predictors and validated by another independent external validation set. Our study indicates the prediction of toxicity could be possible upon predose metabolic profile. Pharmacometabolomics can be a potentially useful tool for complicating toxicity prediction. Our findings also provide a new insight into CPT-11 precision medicine. KEY WORDS: Irinotecan, Individual differences, Complicating toxicity, Prediction, Metabolomics, Gastrointestinal toxicity, Biomarkers, Diarrheahttp://www.sciencedirect.com/science/article/pii/S2211383518304453 |
| spellingShingle | Yiqiao Gao Wei Li Jiaqing Chen Xu Wang Yingtong Lv Yin Huang Zunjian Zhang Fengguo Xu Pharmacometabolomic prediction of individual differences of gastrointestinal toxicity complicating myelosuppression in rats induced by irinotecan Acta Pharmaceutica Sinica B |
| title | Pharmacometabolomic prediction of individual differences of gastrointestinal toxicity complicating myelosuppression in rats induced by irinotecan |
| title_full | Pharmacometabolomic prediction of individual differences of gastrointestinal toxicity complicating myelosuppression in rats induced by irinotecan |
| title_fullStr | Pharmacometabolomic prediction of individual differences of gastrointestinal toxicity complicating myelosuppression in rats induced by irinotecan |
| title_full_unstemmed | Pharmacometabolomic prediction of individual differences of gastrointestinal toxicity complicating myelosuppression in rats induced by irinotecan |
| title_short | Pharmacometabolomic prediction of individual differences of gastrointestinal toxicity complicating myelosuppression in rats induced by irinotecan |
| title_sort | pharmacometabolomic prediction of individual differences of gastrointestinal toxicity complicating myelosuppression in rats induced by irinotecan |
| url | http://www.sciencedirect.com/science/article/pii/S2211383518304453 |
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