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Congratulations Dr. Dong, your manuscript has been accepted for publication.
[# PeerJ Staff Note - this decision was reviewed and approved by Vladimir Uversky, a PeerJ Section Editor covering this Section #]
All Comments Cleared
Good
Good
Accetable in the present form
Dear authors, based on the recommendations of the reviewer, I would request you to re-submit your manuscript after minor revisions requested by Reviewer 3.
There are no further comments. Everything was written well and clearly, with solid scientific literature related to the main topic. Every comment and all inquiries were amended and answered.
The study is well-designed and structured. The study questions are clear and relevant to the main topic, and the objectives are targeted. The study provided knowledge about a new and possible drug-drug interaction between sorafenib & SGLT2 inhibitors. The methodology seems reproducible, with good reporting of the most relevant points in experimental procedures. Every comment in this part was amended and answered
The results are valid and statistically sound, and they report new findings. The most relevant findings were well discussed and explained, supported by appropriate references. The conclusion was concise, highlighting the important findings and completing the research objectives. Again, all comments and inquiries were amended and answered.
There are no further comments regarding the manuscript. I appreciate the authors for answering all the comments and inquiries placed on the manuscript.
all coments are justified
Clarifying the rationale for only using mRNA data even more briefly in the discussion, tying it back to pharmacokinetics vs. pharmacodynamics.
Providing a short supplementary figure or schematic summarising the interaction pathways involving the studied transporters (UGT, OATP1B2, P-gp), even if based only on mRNA results. This could visually reinforce the gene-expression impact without needing WB data.
Clear
Clear
Our reviewers have thoroughly evaluated your submission, and based on their input I have decided that your manuscript needs to be revised significantly. While revising please pay attention to the suggestions especially by reviewers 2 and 3. Some of the major revisions in addition to others mentioned in the reviews include fixing the issues with figures, including additional references if you think they are appropriate, addressing the questions on statistics, making background concise, providing clarifications and justifications wherever requested.
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Male Sprague-Dawley (SD) rats were divided into seven groups (n=6) that received: sorafenib (1), empagliflozin (2), henagliflozin (3), empagliflozin and sorafenib (4), henagliflozin and sorafenib (5), sorafenib and empagliflozin (6), sorafenib and henagliflozin (7). Blood samples were collected at multiple time points to measure plasma drug concentrations using UPLC-MS/MS, and pharmacokinetic parameters were calculated. In addition, messenger RNA (mRNA) expression was measured by quantitative polymerase chain reaction (RT-qPCR) to explore underlying mechanisms of interaction. Data analyses were conducted using DAS 2.1.1 Software. A p-value of)<)0.05 was used as the level of statistical significance.
The study revealed that sorafenib slightly increased the plasma concentration-time curves (AUC0-t and AUC0ñ>) of empagliflozin, whereas the apparent clearance (CLz/F) and apparent volume of distribution (Vz/F) significantly decreased. Similarly, sorafenib increased the AUC0-t, AUC0-> and the maximum plasma concentrations (Cmax) of henagliflozin and decreased the CLz/F. Besides, coadministration of empagliflozin decreased the CLz/F, increased the AUC0ñ> and Cmax of sorafenib When coadministered with henagliflozin, the AUC0-t and AUC0ñ> of sorafenib significantly increased by 67% and 80%, respectively, accompanied by decrease in the CLz/F. Furthermore, PCR results demonstrated that sorafenib decreased the expression of Ugt2b7 in intestinal tissue. Empagliflozin and henagliflozin inhibited Oatp1b2 expression in the liver and P-gp expression in the liver and intestines.
No figure 6 in the paper. And, please add the WB results of this study.
the basic reporting was structured clearly, including clear and scientific English language, a topic-relevant literature review, and relevant results. Figures need to be revised in certain points:
1- Remove figure title (Data1) from Figure 5
2- The “results” section is written well, easily going, and understandable, highlighting the most important outcomes. Figure 3 needs more explanation in the caption. Why are there 2 figures, one inside the other, in one image? If they represent different outcomes, mark each one with a letter and explain in the caption
3- All included figures need a caption highlighting the sample size, significance level, data presentation (e.g.: mean ± SEM), and statistical analysis method
4- I couldn’t find Figure 6, which you mentioned and cited in the text, the one representing the gene expression analysis. Please make sure that all figures cited are included in the manuscript.
1- In the “Animals” sub-section, rats age must be specified
2- Mention the route and frequency of administration of your test agents in the “pharmacokinetic study” sub-section
3- It is for better and easier understanding if you provide a study design flowchart highlighting the exact timeline of the study with the interventions
4- Line 149, “The doses were chosen by converting the clinically recommended doses for patients to animal doses”. Add equation, conversion factor, and reference.
Nair, A. B., & Jacob, S. (2016). A simple practice guide for dose conversion between animals and humans. Journal of Basic and Clinical Pharmacy, 7(2), 27. https://pmc.ncbi.nlm.nih.gov/articles/PMC4804402/
5- Line 197, I think you mean “henagliflozin” instead of “empagliflozin”. Please check
1- In the “statistical analysis” section, why did you estimate the sample size for the experiment using the resource equation method and not using the statistical G*Power 3 analysis program for precise estimation?
Faul F, Erdfelder E, Lang AG et al (2007) G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods. 39:175–191. https://link.springer.com/article/10.3758/BF03193146
2- Please justify the relationship between UGT1A7 and UGT1A9 and the functional role of UGT1A7 on the metabolizing activity of UGT1A9 clearly since you explained the importance of UGT1A9 in the “Introduction” whereas you investigated the molecular expression of UGT1A7
1- The “background” part needs to be shorter in the abstract. Remove lines 11 & 12 (starting with empagliflozin and ending with (T2DM)). Remove lines 14,15, & 16 (starting with previous studies and ending with SGLT2 inhibitors). Rephrase the aim (lines 16 & 17) to be (this study aimed to investigate the pharmacokinetic profiles of coadministration of sorafenib with novel SGLT2 inhibitors, either empagliflozin or henagliflozin and to explore their potential mechanisms)
2- Remove all unnecessary abbreviations in the abstract, since you’ve given their definition
3- Make sure all abbreviations used regularly are defined at their first appearance
4- In the “introduction” section, lines 117 – 119 starting with (pharmacokinetic parameters till the end of the paragraph) should be removed because they are unrelated to the objectives
**PeerJ Staff Note:** It is PeerJ policy that additional references suggested during the peer-review process should only be included if the authors are in agreement that they are relevant and useful.
1. The manuscript is written in professional English, but there are minor typographical errors and inconsistencies in drug names (e.g., “empagliûozin” should be “empagliflozin”). Please ensure consistency throughout the text.
2. The introduction provides relevant background, but additional references could strengthen the discussion on pharmacokinetic interactions of TKIs and SGLT2 inhibitors.
3. Figures and tables are relevant and well-labeled. However, ensure that images are of high resolution and clearly depict the findings.
4. Raw data has been provided. It should be checked against the results for accuracy.
5. The research question is well-defined and meaningful, addressing an important pharmacokinetic interaction.
6. The methodology is generally well-described, allowing replication. However, additional details on how dose selection was determined relative to human-equivalent doses would improve clarity.
7. Ethical approval has been mentioned, but it would be helpful to clarify whether all experiments align with international guidelines on animal research.
8. The data is robust, with statistical analysis applied appropriately. However, it would be beneficial to provide a justification for the sample size used—was a power calculation performed?
9. The discussion provides a well-linked interpretation of findings, but more emphasis on clinical relevance (e.g., toxicity implications of drug interactions) would improve the impact.
10. The limitations are acknowledged (e.g., lack of HCC and T2DM animal models). It would be useful to suggest how future studies could overcome these challenges.
1. The manuscript presents valuable insights into drug-drug interactions that may affect clinical dosing guidelines.
2. While the study is technically sound, some areas need clarification, including:
Justification for dosage selection
More discussion on transporter inhibition mechanisms
Potential clinical consequences of altered pharmacokinetics.
• The manuscript is scientifically valid and well-organized but requires minor revisions for language clarity and data interpretation.
• The ethical approval statement is present, but it should be ensured that all journal policies on vertebrate animal research are followed.
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