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Predicting the presence and mechanism of busulfan drug-drug interactions in hematopoietic stem cell transplantation using pharmacokinetic interaction network–based molecular structure similarity and network pharmacology

  • Pharmacokinetics and Disposition
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Abstract

Purpose

This study aimed to predict the presence and mechanism of busulfan drug-drug interactions (DDIs) in hematopoietic stem cell transplantation (HSCT) using pharmacokinetic interaction (PKI) network–based molecular structure similarity and network pharmacology.

Methods

Logistic function models were established to predict busulfan DDIs based on the assumption that an approved drug tends to interact with the drug used in HSCT (DH) if structurally similar to the drugs in the PKI network of the DH. The PKI network of the DH represented the association between drugs and the proteins related to the PK of the DH. The most appropriate model was applied to predict busulfan DDIs in HSCT. Candidate targets for busulfan DDIs and their interacting were identified by network pharmacology.

Results

Six of the top ten predicted busulfan DDIs were clinically relevant and involved voriconazole, fludarabine, itraconazole, cyclophosphamide, metronidazole, and melphalan. Candidate targets for these DDIs were CYP450s (3A4, 2B6, 2C9, and 2C19), GSTs (GSTA1, GSTP1, GSTT1, and GSTM1), and ABC transporters (ABCB1, ABCC1, ABCC2, and ABCC3), in the targets of drug-induced liver injury (DILI). The networks of interacting proteins and candidate targets indicated the regulatory potential of pregnane X receptor (PXR), as a nuclear receptor. Enrichment analysis showed the metabolism of drugs and xenobiotics, glutathione metabolism, and bile secretion associated with busulfan DDIs and DILI.

Conclusions

This study has successfully predicted busulfan DDIs in HSCT through PKI-based molecular structure similarity. The mechanism of busulfan DDI and DILI was attributed mostly to CYP450s, GSTs, and ABC transporters, and PXR was identified as a potential target.

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Funding

This work was funded by the National Natural Science Foundation in China (Grant No. 81503137).

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Author notes

  1. Chenxia Hao and Xiaoqin Ma contributed equally to this work. Wanhua Yang and Jingjing Huang were the co-corresponding author for this work.

Authors and Affiliations

  1. Department of Pharmacy, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Chenxia Hao, Xiaoqin Ma, Weixia Zhang, Jingjing Huang & Wanhua Yang

  2. Department of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Lining Wang & Jiong Hu

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  1. Chenxia Hao
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Contributions

Chenxia Hao designed the study and wrote the manuscript. Xiaoqin Ma performed the study and wrote the manuscript. Wanhua Yang and Jingjing Huang regulated the entire project and reviewed the manuscript. Jiong Hu, Lining Wang, and Weixia Zhang analyzed the data and interpreted the results.

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Correspondence to Wanhua Yang.

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Hao, C., Ma, X., Wang, L. et al. Predicting the presence and mechanism of busulfan drug-drug interactions in hematopoietic stem cell transplantation using pharmacokinetic interaction network–based molecular structure similarity and network pharmacology. Eur J Clin Pharmacol 77, 595–605 (2021). https://doi.org/10.1007/s00228-020-03034-4

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