Drug-Food Interactions with a Focus on Mediterranean Diet

Round 1

Reviewer 1 Report

This manuscript deals with the drug-food interactions (DFIs) focusing on examples of foods that are included in the Mediterranean diet (Med-D) habits and discuss cases that they can be related with significant DFIs. DFIs for Med-D food products are associated with modulation of pharmacokinetic processes and primarily with drugs’ first pass effect from the gastro-intestinal tract (GI-track) to reach the systemic circulation. In addition, the paper discusses current evidence for food products that are included within the Med-D and available scientific data suggesting potential contribution in DFIs with significant impact on therapeutic outcome.

The paper points out that for Mediterranean diet (Med-D), one of the most effective diets, there can be cases where food habits may have negative impact on therapeutic outcome. Proper patient consultation is important, so they are aware to avoid any potential conflicts between administered treatment and dietary habits. Adherence to a diet program as the one that is proposed through Med-D and individualized patient consultation and education from healthcare providers for potential DFIs will help patients to manage their disease and their overall well-being.

It is a well-written article with interesting data and considerations.

Nonetheless:

There are many publications in the literature which relate the anti-inflammatory action of Mediterranean Diet with the potent inflammatory mediator Platelet Activating Factor (PAF) and the existence of anti-inflammatory micronutrients (PAF-inhibitors) in the foods of Mediterranean Diet (the existence of specific polar lipids that modulate PAF action and metabolism) as well as they relate the Mediterranean Diet with diseases. Indicatively, I mention the article

            -Mediterranean diet and platelet-activating factor; a systematic review. Clinical             Biochemistry, 60, Pages 1-10, 2018,

            Nomikos, T., Fragopoulou, E., Antonopoulou, S., Panagiotakos, D.B

which it should be at least mentioned, where there are the phrases " Moreover, for Med-D food products we can recognize specific active constituents (i.e., oleuropein, resveratrol, retinoids, flavonoids, terpenes, catechins, ω-3-fatty acids etc.) with pharmacological effects (i.e., anti-oxidant and anti-inflammatory) that are related with the health benefits from adherence in Med-D [22–30]." and/or " It is of no debate that a healthy diet and nutrition is essential for good health and shields from several chronic non-communicable diseases, such as cardiovascular heart disease, diabetes, CNS disorders, autoimmune disease and cancer [11,15,22,26,171–173]. "

Furthermore, the paper makes no reference to the subsection (2.1.3. Metabolism) in another dimension of the beneficial effect of PAF inhibitors in the pharmacological action of specialized drugs for each disease, that they inhibit the action of cytochrome P450 which contributes to the degradation of the active compound of the drug and consequently to the shorter time of action in the body.

It has been known from decades about the existence of PAF endogenously in photosystems in plants and the role of PAF in the organization of photosystems. It was later suggested that PAF was also involved in the activation of ATP-dependent H+ transport in microsomes and that PAF is involved in other electron transfer processes, such as that with P450. In fact, the view is expressed that PAF inhibitors inhibit the action of P450 and vice versa. That is, PAF inhibitors inhibit the action of P 450 as in the well-known case usually cited of Cedrol which is a naturally occurring sesquiterpene alcohol, which is a potent competitive inhibitor of P450 as well as of PAF.

Indicatively, I mention the bibliography

- Regulation of Choloroplast Biogenesis (Book 1992)

Editors. Joan H. Argyroudi-Akoyunoglou

Part of the book series: NATO Science Series A: (NSSA, volume 226)

Proceedings of a NATD Advanced Research Workshop on Regulation of Chloroplast Biogenesis, held July 28-August 3,1991, in Crete, Greece

- Phospholipid-stimulated protein kinase in plants

G Martiny-Baron, G F Scherer

J Biol Chem (1989) Oct 25;264(30):18052-9.

PMID: 2530218

- Cytochrome P-450-dependent metabolism in alveolar type II epithelial cells: modulation by platelet-activating factor

J Rabovsky, W H Pailes, D J Judy, V Castranova

Biochim Biophys Acta  (1991) Nov 12;1095(3):223-9.

PMID: 1958697 DOI: 10.1016/0167-4889(91)90103-5

Author Response

We would like to thank the reviewer for the very positive feedback and the constructive comments on our work. They will help us improve further our manuscript.

1. We have included the relative reference in the mentioned sections in our MS. The work from Nomikos et al.,Mediterranean diet and platelet-activating factor; a systematic review. Clinical Biochemistry, 60, Pages 1-10, 2018 is now reference 31 in our text.
2. The subsection “2.1.3. Metabolism” briefly describes the main metabolic pathways for xenobiotics and specifically for drug molecules. It was not designed or written in the point of view of cellular metabolism.

P450 located in the inner membrane of mitochondria or in the endoplasmic reticulum metabolize endogenous and exogenous chemicals. CYPs catalyze about 40 different metabolic reactions such as hydroxylation of aromatic and aliphatic chemical molecules, N- and O-dealkylation of secondary and tertiary amines and O-methyl or ethyl derivatives, the β-cleavage of hydroperoxides, etc. The general route is 1) Binding of the R-H substrate to the active site of P450 (2) Reduction of Fe³⁺ of the heme group to Fe²⁺ via one-electron transfer, (3) Binding of activated O₂ to Fe²⁺ and formation of a P450-O₂ complex, (4) Reduction of O₂ via transfer of an electron and attachment of H to an O atom (5) Addition of an H atom and removal of an H₂O molecule and reaction of the R-H substrate with O* (6) removal of the oxidized substrate and regeneration of P450.

P450 is also the main metabolic oxidation pathway (phase I) for drugs which it takes place mainly in the liver (and in lesser extent in other tissues). As we state “Cytochromes P450 (CYPs) are responsible for 80% of the total phase I oxidation reactions [84]. Of the total 18 CYP families described in humans the first three participate mostly in drug metabolism. In our section we focus on metabolism of exogenous chemicals and mainly on drug mediated metabolism from CYP3A4/5, CYP2D6, CYP2C8/9, CYP2C19, CYP2E1, CYP1A1/2, and CYP2B6. So from the total superfamily of enzymes we refer to only 8-10 that play role in drug metabolism. From the point of pharmacokinetics this is part of drug’s intrinsic clearance. Hepatic intrinsic clearance (CLint) is the main parameter that relates to hepatic extraction (E) and hence systemic clearance CLs and hepatic first-pass effect (F):[1]E=fuxCLi/fu x CLi+Q_H where fu is fraction unbound in blood and Q_H is liver blood flow (Comprehensive Medicinal Chemistry II, 2007). So whenever we refer to metabolism and DFIs we refer mostly to constituents that impact the intrinsic clearance (i.e., the specific P450 isoenzymes). 

Regarding the role of PAFs there is a lot of literature to cover the issue of their effects on human body. There are a lot of works regarding edible plants and/or their isolated compounds on the modulation of platelet function, hemostasis and thrombosis (Int. J. Mol. Sci. 2022, 23(2), 605; https://doi.org/10.3390/ijms23020605). We make a brief passage regarding inhibition of platelet activation by omega-3 polyunsaturated fatty acids. “Regarding DFIs, omega-3 FAs seem to reduce coagulation factors (i.e., fibrinogen and prothrombin) thus in theory can potentiate the effects of anticoagulants [156]”. We also add a relative section in the end of 3.3.1vegetables, herbals, olive oil, cereals and nuts where we mention also cedrol.  As the reviewer pointed out, it is well-known the existence of molecules with PAF activity endogenously in photosystems in plants and their role in the organization of photosystems i.e., regulating CYP450 activity. We believe though that this very interesting topic that was brought to our attention refers mostly to plants’ organization and less in our work. Indicatively:

• The book from Argyroudi-Akoyunoglou, J.H. Regulation of choloroplast biogenesis. 1992, 644. states (quoting) "New findings that emerge gradually unravel the regulatory mechanisms involved in the assembly, stabilization and growth of the photosynthetic units in thylakoids, the signal transduction chain leading from photoreception to gene expression, the transport of nuclear-coded proteins into stroma-soluble supramolecular enzyme complexes as well as thylakoid-bound supramolecular complexes, involved in light-energy transduction."
• The work J Biol Chem (1989) Oct 25;264(30):18052-9. PMID: 2530218 is using plant material and comments (quoting) "Stimulation of ATP hydrolysis by PAF was observed both in tonoplast- and plasma membrane-containing fractions."
• The work from Rabovsky et al Biochim Biophys Acta. 1991 (quoting) refers to "xenobiotic metabolism in alveolar type II cells can be modified by an inflammatory mediator, such as PAF, produced by alveolar phagocytes". These are intrinsic factors and mechanisms.

Regarding Cedrol there are works for its inhibitory capacity against P450 (i.e., J Toxicol Environ Health A. 2014;77(22-24):1522-32. doi: 10.1080/15287394.2014.9559). Cedrol however is used mainly in cosmetics. We focus (as it is in page 3) on food constituents that are i) present in fair amounts in the food product; ii) reach the shared biological pathway in an adequate concentrations and iii) modulate in a meaningful way drug’s pharmacological action[49,50].  We are not sure that cedrol fulfills all 3 requirements but we added a relative as it was suggested.

We hope that our response will address the comments raised especially for PAF inhibitors.

Reviewer 2 Report

1. There is not continuous line numbers of the manuscript, and actually it is hard to point to the place where need to be revised.

2. The abstract need to be improved. The authors used much words to introduce the background of the present work instead of the main content of this review paper, as well as the conclusions that have drawn after the literature reviewing.

3. I am wonder what is the “drug-food interactions”? is this a general and widely accepted term that used to describe the interactions between the drug and food? The authors are suggested to give more introduction in the introduction part.

4. As we know, the Mediterranean diet is a mixture of different kinds of food ingredients, such as vegetables, legume, milk, red wine, etc. They have been suggested to have a widely variety of health beneficial roles for the humans and is regarded as “super diet”. Therefore, the health benefit of Mediterranean diet seems not owning to this type of diet, but the individual components, or their optimal combination. When discussing their effects, please be aware of this point.

5. After each section of the of the literature reviewing, the authors are suggested to give a short summarization, the unsolved problems of the previous studies or the future research directions are encouraged to provide, not just paraphrasing the studies of the previous work.

6. I also encourage the authors to add a short section in the end of part 3 that summarize and discuss the shortcomings or problems of the Mediterranean diet in the drug-food interactions. This may be necessary for the authors to get more knowledge of this kind of diet, and pay attention to their shortage in some related areas.

7. The language of the present manuscript need to be improved. There are many long sentences that make it hard to follow.

Author Response

We would like to thank the reviewer for the constructive comments and suggestions. We hope that the comments are addressed, and our MS further improved.

• We apologize for any inconvenience regarding the page and numbering of the article. The pdf file that we submitted was using journal’s template and the pdf version (at least to us) shows page and numbers as it should (26 pages, 1105 lines). If any error occurred during text transformation from the platform or elsewhere we apologize from our behalf. Please see also the revised pdf version where the lines and numbers are there.
• Abstract is edited pointing out the main contents of the review.
• We edited the text to place more definitions in the introduction section as well as later in the text. “A DFI describes the physical, biochemical or physiological modulation of a pharmacological process that a drug is following due to the presence of one or more constituents within a food product, nutraceutical or dietary supplements”. We move this phrase from section 2 back to introduction. We added another reference for reviewer’s convenience. Drug-drug interactions and drug-food interactions are widely accepted term. For additional descriptions see references (included in our text):
  • Frankel, E.H.; McCabe, B.J.; Wolfe, J.J. Handbook of food-drug interactions; 2003; ISBN 1135504571.
  • Lopes, M.; Coimbra, M.A.; Costa, M. do C.; Ramos, F. Food supplement vitamins, minerals, amino-acids, fatty acids, phenolic and alkaloid-based substances: An overview of their interaction with drugs. 2021, doi:10.1080/10408398.2021.1997909. 
  • Won, C.S.; Oberlies, N.H.; Paine, M.F. Mechanisms Underlying Food-Drug Interactions: Inhibition of Intestinal Metabolism and Transport. Pharmacol. Ther. 2012, 136, 186, doi:10.1016/J.PHARMTHERA.2012.08.001.
  • Vizirianakis, I.S.; Spanakis, M.; Termentzi, A.; Niopas, I.; Kokkalou, E. Clinical and pharmacogenomic assessment of herb-drug interactions to improve drug delivery and pharmacovigilance. In Plants in Traditional and Modern Medicine: Chemistry and Activity; Kokkalou, E., Ed.; Transworld Research Network: Kerala, India, 2010 ISBN 978-81-7895-432-5.
  • Spanakis, M.; Sfakianakis, S.; Sakkalis, V.; Spanakis, E.G. PharmActa: Empowering Patients to Avoid Clinical Significant Drug-Herb Interactions. Med. 2019, 6, doi:10.3390/medicines6010026
  • Spanakis, M.; Sfakianakis, S.; Spanakis, E.G.; Kallergis, G.; Sakkalis, V. PDCA: An eHealth service for the management of drug interactions with complementary and alternative medicines. In Proceedings of the 2018 IEEE EMBS International Conference on Biomedical and Health Informatics, BHI 2018; 2018; Vol. 2018-Janu

4. We thank the reviewer for this comment. Our work is focusing on this issue solely and we try to structure accordingly our manuscript. Med-D is a “super diet” with a plethora of food products so the question that we try to answer is more or less summarized in “Which foods that are included in Med-D can modulate drugs’ action?” Till today most of the studies are focusing -and they right to do so- to the beneficial effects of Med-D. But what about the issue of drug-food interactions? As we note in the updated abstract "Med-D is well-known to promote well-being and lower the risk for chronic conditions such as cardiovascular diseases, diabetes, and metabolic syndrome. On the other hand, bio-active constituents in foods, except of their beneficial effects may interfere with drugs' pharmacological mechanisms, modulating the clinical outcome leading to drug-food interactions (DFIs).” For example, how safe is for a patient with cardiovascular disease and dyslipidemia to consume grapefruit and employ oat brans and fibers if he/she is prescribed with statins and amlodipine? The answer is that he/she will be in risk of ADRs from both medications. So we do not discuss the Med-D in total but we try to focus on specific examples.
5. We would like to be pointed out for section is the question referred to. Examples of short summarization can be found in our text. Maybe not a distinct paragraph in the end, but surely there. We give some examples:
   • ...Thus, healthcare advice is needed in cases patients habitually consume excessive amounts of vegetables such as broccoli, Brussels sprout, cabbage, cauliflower, radish, and watercress and are under treatment with CYP1A2 substrates (i.e., clozapine, olanzapine, fluvoxamine, haloperidol, melatonin, ramelteon, tizanidine, and theophylline)....
   • .... As a result, the often consumption of these products alerted the previous years the scientific community to examine if DFIs could be further observed....
   • ...observational studies suggest that adherence to Med-D improves survival for CKD patients, there is a lack of conclusive clinical data regarding DFIs and hyperkaliemia and till then vigilance should be advised from healthcare providers
   • ..Considering also that dietary supplements have usually a higher content of n-3 FAs that the consumed food, the potential DFI is of minor importance and negligible for patients that remain adherent in their treatment plan.
   • ...milk and dairy products are an old case of potential DFIs due to their content in Ca2+ and tyramine
   • ...high-fat content may lead in raised salt and increase the solubilization of lipophilic drugs [38]
   • The potential interactions of drugs with alcohol are well-known and described through literature.

To address the comment we edited further the discussion section. The main issue of drug-food interactions is the lack of available clinical data consider the evidence based hierarchy. In tables 1-3 there are a lot of theoretical and in vitro observations. For the last part of the question, is the reviewer referring to any plagiarism issue because we did not get notified for anything like that so we believe we do not simple “paraphrasing” in our text.  

6. This is a similar issue with comment 5 and we try to resolve it as we described in our answer there. We did that in the discussion section where we reference the tables and figures previously in the text. Placing it in the end of section 3 (before the discussion) it will reduce the details of discussion or repeat some things making text tedious and difficult to read. We apologize but we do not fully understand the comment “the authors to get more knowledge of this kind of diet”. Regarding differences among the Mediterranean basin, even from the introduction we state, “The analysis focuses on the most common and known food products considering cultural, ethnic, agricultural variations among the regions around Mediterranean area which ac-count for alterations in Med-D dietary habits.”
7. The text was further edited to shorten sentences along with English language edits. See tracked-changes text for comparison.