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  • Anna Gumieniczek * and
  • Anna Berecka-Rycerz

Reviewer 1: Xin Chen Reviewer 2: Juei-Tang Cheng

Round 1

Reviewer 1 Report

This manuscript reviewed the analytical approaches for examining the metabolism and degradation pathways of glucagon like peptide 1 (GLP-1) receptor agonists and sodium glucose co-transporter 2 (SGLT2) inhibitors.

A few concerns for the authors.

1.       The authors claimed in the abstract part that they would have a Part II which focused on metabolism and degradation pathways of gliptins that are dipeptidyl peptidase 4 (DPP-4) inhibitors but there actually was not such information included in this manuscript.

2.       The manuscript tried to describe the metabolism and degradation pathways for GLP-1 receptor agonists and SGLT-2 inhibitors, but no pathway had been presented. Instead of having tables listing the metabolites and degraders, it would be better to list the metabolic pathways and degradation pathways associated with these drugs and showed the enzymes involved. So Table 2, Table 3, Figures 3, 4, and 5 need to be reorganized.

3.       The authors also claimed at the beginning that metabolic pathways and degradation pathways usually overlap and form similar constituents. How can the authors surely declare that some of the analogs formed from metabolic pathways and the others from degradation pathways. Some of the metabolic enzymes can have the capacity to generate some, if not all, of the degradation compounds listed in the manuscript.

English is fine with minor editing.

Author Response

Reviewer 1

  1. The authors claimed in the abstract part that they would have a Part II which focused on metabolism and degradation pathways of gliptins that are dipeptidyl peptidase 4 (DPP-4) inhibitors but there actually was not such information included in this manuscript.

Answer

The part II of our paper entitled “Metabolism and chemical degradation of new antidiabetic drugs (Part II): a review of analytical approaches for analysis of gliptins” has been submitted simultaneously to the same Special Issue of Biomedicines, with permission from the Editors, and is in the review process now.

  1.  

The manuscript tried to describe the metabolism and degradation pathways for GLP-1 receptor agonists and SGLT-2 inhibitors, but no pathway had been presented. Instead of having tables listing the metabolites and degraders, it would be better to list the metabolic pathways and degradation pathways associated with these drugs and showed the enzymes involved. So Table 2, Table 3, Figures 3, 4, and 5 need to be reorganized.

Answer

According to Reviewer's suggestion, the most important metabolic and degradation pathways for gliflozins are now presented in new figures. As a consequence, Table 2 and Table 3 were reorganized as well as the previous Figure 4. However, previous Figure 3 and Figure 5 are still present in our manuscript, because we would like to emphasize some similar pathways between the mentioned gliflozins, as well for metabolic as for degradation changes.

  1.  

The authors also claimed at the beginning that metabolic pathways and degradation pathways usually overlap and form similar constituents. How can the authors surely declare that some of the analogs formed from metabolic pathways and the others from degradation pathways. Some of the metabolic enzymes can have the capacity to generate some, if not all, of the degradation compounds listed in the manuscript.

Answer

Indeed, drug metabolism in the body and drug degradation during processing and/or storage can undergo similar chemical reactions. Consequently, many impurities generated during degradation are also metabolites and vice versa. Thus, the goal of the present study was to emphasize this fact, and to verify the possibility that such processes occur for many important drugs, for example, gliflozins. When looking for the above connections and similar products of both metabolism and degradation, we intended to find as many as possible to express the idea of devising future studies connecting these two essential aspects of every type of therapy. Such results can be used for various purposes. For example, for toxicological assessment and qualification of impurities. It is obvious that a simple comparison of an impurity with a detected metabolite in humans or animals is not adequate to qualify an impurity. This is because the detected compound could be a metabolite or an impurity. Therefore, such particular experiments from non clinical studies should be carefully interpreted to answer the question if a total exposure of patient to each specific compound is equal to or greater than the level that might result from the real exposure after particular drug administration.

There is no similar review in the literature concerning these beneficial antidiabetic drugs, in terms of their metabolism and chemical degradation. That is why we drew attention to these important issues and at the same time we discussed the most interesting analytical procedures that can be used for such experiments. The present review could be valuable for researches working on drug metabolism or stability and on biological impact of particular metabolites or degradants.

 

Reviewer 2 Report

Current report investigated the metabolism and degradation pathways of glutides, i.e. glucagon like peptide 1 (GLP-1) receptor agonists, and gliflozins as sodium glucose co-transporter 2 (SGLT2) inhibitors. I like to give the comments below.

1, Current review article collected the published results from various reference(s). How to control the quality of analysis?

2. Both drug metabolism and drug degradation (during drug manufacturing and/or storage) can undergo similar chemical transformations. However, hepatic enzyme induction seems ignored in vivo.

3. Novelty of current review did not show in clear.

4. Limitation(s) of current report will be helpful.

5. How to link to the next report? It seems unknown.

It seems better to check through the professional editing in advance.

Author Response

Reviewer 2

  1. Current review article collected the published results from various reference(s). How to control the quality of analysis?

Answer

First of all, our review includes the published projects that have been made using modern analytical tools. Secondly, during the literature examination, we paid attention, wherever possible, to validation parameters of particular analytical methods proposed in the mentioned projects. In addition, when the proposed metabolic and degradation pathways were analyzed by us, our attention was drawn to all available references concerning each particular drug.

  1. Both drug metabolism and drug degradation (during drug manufacturing and/or storage) can undergo similar chemical transformations. However, hepatic enzyme induction seems ignored in vivo.

Answer

When reviewing the literature on the metabolism of glutides and gliflozins, we paid close attention to the projects where the effects of various enzymes involved in in vivo reactions were studied. Wherever possible, relevant information was included in the revised text of our paper.

We intended to find as many connections between both drug metabolism and drug degradation as possible to express the idea of devising studies connecting these two essential aspects. Such results can be used for various purposes. Among other things, for toxicological assessment and qualification of impurities. It is obvious that simple comparison of an impurity with a detected metabolite in humans or animals is not adequate to qualify an impurity. This is because the detected compound could be a metabolite or an impurity. Therefore, such particular experiments from non clinical studies should be carefully interpreted to answer the question if a total exposure of patient to each specific compound is equal to or greater than the level that might result from the real exposure after drug administration.

  1. Novelty of current review did not show in clear.

Answer

There is no similar review in the literature concerning these important drugs. That is why we drew attention to these important issues, i.e. metabolism and degradation reactions. At the same time we showed and discussed the most interesting analytical procedures that can be used for such determinations. To better show the novelty of our review some sentences were added in our revised text.

  1. Limitation(s) of current report will be helpful.

Answer

We made effort to keep the text concise as much as possible. On the other hand, we wanted to include all drugs from a given group and not omit any interesting analytical procedures.

In the revised version, some tables and figures were reorganized, which we hope increased the conciseness and coherence of our review.

  1. How to link to the next report? It seems unknown.

Answer

The part II of our review entitled “Metabolism and chemical degradation of new antidiabetic drugs (Part II): a review of analytical approaches for analysis of gliptins” has been submitted simultaneously to the same Special Issue of Biomedicines, with permission from the Editors, and it is in the review process.

  1. Current review article collected the published data to analysis themetabolism and degradation of antidiabetic drugs. It seems interesting in chemical field. However, it failed to associate the data in humans oranimal studies. Therefore, it needs to revise for this weakness.

Answer

Thank you for this suggestion. Where possible we added the results from clinical and pre-clinical studies on animals, especially where previously this data was insufficient. We hope that this significantly increased the value of our article. All changes were marked red in our revised version.

 

Round 2

Reviewer 1 Report

This revised manuscript reviewed the analytical approaches for examining the metabolism and degradation pathways of glucagon like peptide 1 (GLP-1) receptor agonists and sodium glucose co-transporter 2 (SGLT2) inhibitors.

A few concerns for the authors.

1.       If Part II which focused on metabolism and degradation pathways of gliptins that are dipeptidyl peptidase 4 (DPP-4) inhibitors is not included in this manuscript, there is no point of indicate that in the abstract.

2.       Figure 3, ERTU-M1, there should be stereochemistry issue with the second C from the right, just regular single bond.

3.       Figure 4: 1) If the authors would like to indicate the specific drug metabolizing enzymes involved in the metabolic pathways, they should do that for every metabolic reaction. 2) Other CYP450 enzymes like CYP2D6 can also do the dealkylation reaction to generate M1 and M2. 3) For the generation of M5, it is mostly likely CYP450 enzymes instead of “dehydrogenase” which we mostly refer to aldehyde dehydrogenase and alcohol dehydrogenase when we talk about drug metabolism.

4.       Table 2 is having different way of presenting the metabolites, which is not in consistence with the others.

5.       Figure 5: 1) For acid degradation, ether functional groups are not that acid sensitive to acidic environment. It is most likely the CYP450 enzymes doing the O-dealkylation reactions that break the ether functional groups. 2) What is the structure of D3? 3) Where do the Cl atoms come from?

6.       Figure 6: 1) It is not easy to oxidize the OH group to COOH without the metabolizing enzymes to generate D5. 2) It is also not easy to remove Cl without the metabolizing enzymes to generate D4, D5 and D7. 3) Similar as #5, breaking an ether link is not that easy chemically without the enzyme to produce D16.

7.       Table 3 is not in the same format to show the degradation pathways.

8.       Figures 7, 8 and 9 need to be presented in a more clear and concise way.

Author Response

Reviewer 1

This revised manuscript reviewed the analytical approaches for examining the metabolism and degradation pathways of glucagon like peptide 1 (GLP-1) receptor agonists and sodium glucose co-transporter 2 (SGLT2) inhibitors.

A few concerns for the authors.

  1. If Part II which focused on metabolism and degradation pathways of gliptins that are dipeptidyl peptidase 4 (DPP-4) inhibitors is not included in this manuscript, there is no point of indicate that in the abstract.

We agree, all pieces of information on Part II of our review were removed in our revised version.

  1. Figure 3, ERTU-M1, there should be stereochemistry issue with the second C from the right, just regular single bond.

We agree, Figure 3 was corrected.

  1. Figure 4: 1) If the authors would like to indicate the specific drug metabolizing enzymes involved in the metabolic pathways, they should do that for every metabolic reaction. 2) Other CYP450 enzymes like CYP2D6 can also do the dealkylation reaction to generate M1 and M2. 3) For the generation of M5, it is mostly likely CYP450 enzymes instead of “dehydrogenase” which we mostly refer to aldehyde dehydrogenase and alcohol dehydrogenase when we talk about drug metabolism.

We agree. Thank you for these comments. Figure was corrected and all the main enzymes mentioned in the given reference [38] were added. As far as M5 is concerned and dehydrogenase, it was wrong in our previous figure. It was corrected in our revised version. We are very sorry for this error.

  1. Figure 5: 1) For acid degradation, ether functional groups are not that acid sensitive to acidic environment. It is most likely the CYP450 enzymes doing the O-dealkylation reactions that break the ether functional groups. 2) What is the structure of D3? 3) Where do the Cl atoms come from?

D3 degradant could be described as 6-(4-chloro-3{[4-(oxalan-3-yloxy)phenyl]methyl}phenyl)-2-methylidene-2H-pyran-3-ol. The structure was corrected in our revised Figure to better show the methylidene group.

Degradation of empagliflozin through spliting the ether linkage was described in the cited papers [46, 47, 48], probably due to the presence of strong acid like HCl, as well as possibility of chlorination of the phenyl ring.

  1. Figure 6: 1) It is not easy to oxidize the OH group to COOH without the metabolizing enzymes to generate D5. 2) It is also not easy to remove Cl without the metabolizing enzymes to generate D4, D5 and D7. 3) Similar as #5, breaking an ether link is not that easy chemically without the enzyme to produce D16.

Figure was based on the results obtained in Refs. 47 and 48. D4, D5, D7 and D16 as well as the rest of degradants were detected in the samples stressed in extreme conditions, i.e. strong acidic, strong alkaline and strong oxidative conditions, 2-5M HCl, 2-5M NaOH and 30% H202 at 60-80°C. Such severe stress is often used in drug stability experiments, to maximize the numer of potential degradants.

  1. Table 3 is not in the same format to show the degradation pathways.

We agree. Table 2 and Table 3 were deleted and all the information was removed to the respective Figures.

  1. Figures 7, 8 and 9 need to be presented in a more clear and concise way.

Figures were corrected. We hope that are more clear and, at the same time, more informative.

Round 3

Reviewer 1 Report

A couple of issues for the authors.

1.       Figure 6, ERTU-M1, there should be stereochemistry issue with the second C from the right, just regular single bond.

2.       Figures 5, 6 and 8, some of the metabolites with m/z values indicated “n. a.”, what does “n. a.” mean? How can m/z values be “n. a.”?

 

Author Response

Reviewer 1:

A couple of issues for the authors.

  1. Figure 6, ERTU-M1, there should be stereochemistry issue with the second C from the right, just regular single bond.
  2. Figures 5, 6 and 8, some of the metabolites with m/z values indicated “n. a.”, what does “n. a.” mean? How can m/z values be “n. a.”?

 

Answers:

Ad. 1. The structures of ERTU-metabolites and their stereochemistry have been checked and corrected in Figure 6 and Figure 16.

Ad. 2. Figures 5, 6 and 8, which included: “m/z n.a.” have now been corrected. Previously “m/z” meant the values we were not able to find in the cited references.

Thank you very much for your valuable suggestions. We are very sorry for the errors in our figures.

Anna Gumieniczek