Predicting the presence and mechanism of busulfan drug-drug interactions in hematopoietic stem cell transplantation usin
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PHARMACOKINETICS AND DISPOSITION
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 Chenxia Hao 1 & Xiaoqin Ma 1 & Lining Wang 2 & Weixia Zhang 1 & Jiong Hu 2 & Jingjing Huang 1 & Wanhua Yang 1 Received: 21 June 2020 / Accepted: 30 October 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
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. Keywords Busulfan . Drug-drug interactions . Pharmacokinetics . Structural similarity . Network pharmacology . Hematopoietic stem cell transplantation
Introduction Chenxia Hao and Xiaoqin Ma contributed equally to this work. Wanhua Yang and Jingjing Huang were the co-corresponding author for this work. * Wanhua Yang [email protected] Jingjing Huang [email protected] 1
Department of Pharmacy, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
2
Department of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Hematopoietic stem cell transplantation (HSCT) represents an effective treatment for numerous malignant and nonmalignant diseases [1]. Busulfan (1,4-butanediol dimethanesulfonate) is widely used as a pre-transplant conditioni
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