Evaluation of phenoconversion phenomenon in obese patients: the effects of bariatric surgery on the CYP450 activity “a protocol for a case–control pharmacokinetic study”

Abstract

Personalized therapy suggests the appropriate drug at the right dose for the first time through genotype-based individualized therapy, instead of prescribing medicines by the traditional one-size-fits-all manner, thereby claiming that it will make medicines safer and more effective. Accordingly, polymorphisms of drug metabolizing enzymes (DMEs), which induce inter-individual variability in the pharmacokinetics of a drug, have attracted great interest in the context of personalized medicine.

Obesity is one of the most common chronic diseases in the world, including Iran, and the prevalence is increasing according to predictions. The remarkable role of P450 cytochromes has been verified in the metabolism of numerous drugs, toxins, carcinogen compounds, and the synthesis of some intrinsic compounds, such as steroid hormones. Thus, evaluating the activity of these enzymes is of great importance because any functionality variation can lead to failure in the treatment or unwanted side effects of some drugs.

Therefore, any change in the activity of these enzymes in obese patients can also be problematic in the treatment process of these patients in comparison to normal weighted ones. Since only a few human studies have examined the role of inflammation in altering the function of these enzymes, it seems to be necessary to investigate the effect of obesity on the expression and activity of these enzymes; in which the role of inflammatory processes has been proven.

Most importantly, it is worth evaluating changes in the activity levels of cytochrome P450 (CYP450) and the inflammatory cytokines after a course of post-surgical treatment and weight loss.

To evaluate the activity of CYPs, a multi-drug cocktail is prescribed to obese patients before and after obesity surgery, as well as to healthy volunteers, to provide simultaneous evaluation of different isoforms.

A complete demographic data, medical examinations, laboratory tests, and the CYPs genotype of all participants can be extremely important during this investigation.

Introduction

A phenomenon in which genotypic extensive metabolizers (EMs) are temporarily converted to phenotypic poor metabolizers (PMs) of drugs, potentially with relevant alterations in clinical response, has been termed as phenoconversion. Non-clinical data collected over the last two decades have intensively indicated the down-regulation of drug metabolizing enzymes, particularly the CYP450 family, in the presence of high levels of some pro-inflammatory cytokines, which potentially lead to conditional phenoconversion [1].

Overall, the available information emphasizes the possibility that certain inflammatory circumstances accompanying with high levels of pro-inflammatory cytokines may induce phenoconversion of particular DMEs. Since acute or chronic inflammatory conditions are highly probable, phenoconversion may occur more frequently than it is expected. There is a possibility that concentrating on the genotype of DMEs alone may lead to missing relevant associations between clinical results and DME phenotypes, thus compromising future prospects of personalized medicine [1].

Obesity is a chronic and progressive disease that restricts physical activity and can lead to psychological problems, which has become one of the main health issues worldwide by its growing prevalence [2, 3]. It is obtained from estimates that more than 1 billion adults are overweight, at least 300 million of whom are clinically obese. During the past 20 years, there has been a sudden increase in obesity in the United States [4]. Obesity represents a global epidemic associated with premature mortality and increased risk for type 2 diabetes, cardiovascular disease, and cancer. Weight loss is the initial stage of treatment and even a small weight reduction has beneficial effects on several cardiometabolic complications. It can be achieved by calorie restriction, exercise, pharmacotherapy or bariatric surgery [5]. Therefore, treatment of obesity is among the foremost public health challenges. Treatment should begin with long-term lifestyle interventions, including increased physical activity and dietary changes. Medication may be added for obese people, whose lifestyle modifications alone are not enough. Surgery is an effective treatment option for “morbidly” obese patients who have not been successful in achieving sufficient weight loss with non-surgical strategies [6]. Due to the wide range of these patients, the chance of weight loss after surgical intervention, and the increased demand of bariatric surgery, only patients with “bariatric” surgical indication were enrolled in the current study.

Bariatric surgery is one of the fastest-growing surgical fields in the United States. Sleeve gastrectomy (42.1% of all bariatric cases) and Roux-en-Y gastric bypass (RYGB) (34.2% of all cases) are the most frequent bariatric surgical procedures. Most of this growth is due to their confirmed long-term advantages in the treatment of chronic diseases such as diabetes mellitus, hypertension, and obstructive sleep apnea [7].

Bariatric procedures can be divided into three groups: restrictive, malabsorptive and hybrid operations. One of the most common types of bariatric surgeries implemented worldwide is sleeve gastrectomy (SG) which seems to be a restrictive procedure (less food intake only). This procedure involves the longitudinal excision of the stomach and thus shaping the remaining segment of the stomach into a tube or a “sleeve”-like structure. SG removes approximately 85% of the stomach. In Roux-en-Y gastric bypass (RYGB) which is considered to be a hybrid procedure (less food intake with some degree of malabsorption), the size of the stomach is reduced to that of a small pouch that is directly surgically attached to the lower section of the small intestine. Most of the stomach and the duodenum are surgically stapled and therefore, bypassed in this process [8].

Since pharmacists have the knowledge of medication dosage forms and expertise in disease states influenced by bariatric surgery, they are exclusively responsible for guaranteeing appropriate medication management of a bariatric surgery patient in the ambulatory care setting [7]. In this regard, gathering more information is essential through various studies.

The role of human CYP450 enzymes (CYPs) is noticeable in the metabolism of many endogenous compounds and xenobiotics. The activity of CYPs is influenced by genetic variants, endogenous mediators, and environmental agents such as nutrients, toxins or interacting medications. All these factors are in charge for wide inter-individual differences in plasma drug concentrations, which can be identified either by toxicity or by an insufficient pharmacological response [9].

Although genotyping of DMEs is introduced as a simple approach to estimate the activity of enzymes, phenotyping methods has been developed more recently because of the notable advances in the sensitivity and selectivity of analytical equipment. High performance liquid chromatography coupled with tandem mass spectrometry (LC–MS/MS) makes it possible to measure the actual activity of CYP isoforms in an individual at a given time-point, the information that would be invaluable in the selection of treatments and dose individualization [10].

While the genotyping methods only evaluate the role of genetic factors, phenotyping methods could be applied to simultaneously and quantitatively assess the impact of both genetic and environmental parameters such as drug-drug interactions, disease-state, genetic variants, and other interventions such as bariatric surgery on the activity of DMEs. The cocktail approach, i.e. the administration of a combination of CYP specific probe drugs (substrates of DME), is utilized in order to simultaneously evaluate the activity of many CYP isoforms [10] while it reduces the time and costs, and increases the comfort of patients.

To propose an efficient cocktail, all mutual interactions should be identified. Among all established cocktails, it has been verified that the CYP probes contained within Geneva cocktail do not induce mutual interactions. This puts a high value on the validation of this cocktail, which was proven to impeccably anticipate both normal and altered CYP activities. The combination of a low-dose, high-throughput cocktail with a simple sampling method allows for its application as a phenotyping tool in various settings [11, 12].

In a review, the authors reported altered expression of drug-metabolizing enzymes in animal models of obesity [13]. On the other hand, Park et al. showed that serum levels of some inflammatory cytokines, particularly interleukin (IL)-6 and tumor necrosis factor alpha (TNF-α), were significantly higher in obese patients than in a non-obese group [14].

Therefore, there are previous studies on the relationship between inflammatory cytokines and the expression of P450 enzymes [1] on the one hand, and the obesity and expression of P450 enzymes [13] on the other hand. Accordingly, it can be concluded that changes in the CYPs expression and/or activity are very likely in obese patients, which may occur due to elevated levels of inflammatory cytokines. Furthermore, drug pharmacokinetics may be affected by several factors including alternations in metabolism processes, increased blood volume, liver blood flow, cardiac output, and glomerular filtration, which are detected in obese individuals [15]. Thus, not only should physiological and pathophysiological changes in these patients be considered compared to non-obese individuals, but subsequent changes following rapid weight loss, such as bariatric surgery, are also of great importance in order to reduce treatment failures and avoidable adverse reactions.

The primary objective of our study is to find out the impact of obesity on the activity of six major CYP450 isoforms (CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) and p-glycoprotein following the oral administration of a cocktail of probe drugs in patients with obesity and in non-obese subjects. As secondary objectives, influences of some co-variables, such as inflammatory markers and genetic polymorphisms, as well as demographic and disease-related covariates will be investigated on CYP450 activities.

Study objectives

Differences in liver metabolism are one of the most important factors that causes inter-individual variations. The bibliography of this study suggests that inflammation-related diseases may lead to metabolic changes in individuals. Our knowledge about the activity of enzymes will be helpful in increasing the expected clinical responses while minimizing side effects in patients and facilitating health care delivery. Hence, the effect of obesity on major liver CYP450 activities along with the impact of bariatric surgery on the CYP phenotype alteration pattern will be investigated to evaluate the concept of "phenoconversion".

Methods and analyses

Study design

This research is a single-center, open-label, non-randomized, two-armed (obese and healthy subjects), pharmacokinetic study. The project consists of two major clinical phases. In the first step, the pattern of changes in the phenotypes of six major CYP enzymes and their relationships with other co-variables will be studied in obese patients before and after bariatric surgery. In the second phase, all results will be compared with similar findings in healthy non-obese volunteers. Based on both statistical calculations and literature review, and following approval from the Ethics Review Board, a group of 40 patients of both genders will be enrolled in the first phase. For the second step of the study, a similar number of healthy, non-obese volunteers will be added to the study.

The phenotypes of CYPs enzymes will be assessed through calculating the metabolic ratios of related probes following the oral administration of GENEVA cocktail. The cocktail is composed of 100 mg of caffeine (CYP1A2) (sachet), 25 mg of bupropion (CYP2B6) (tablet), 25 mg of flurbiprofen (CYP2C9) (tablet), 5 mg of omeprazole (CYP2C19) (granules in the capsule), 10 mg of dextromethorphan (CYP2D6) (syrup), 1 mg of midazolam (CYP3A4/5) (liquid formulation), and 25 mg of fexofenadine (P-gp) (tablet).

After determining the phenotypes of these enzymes, the impacts of several principal co-variables such as genotypes and other characteristics associated with the disease will be considered on the activity of measured CYP enzymes as secondary endpoints. These include inflammatory markers (IL-1ß, IL-6 and TNF-α), demographic-related factors (gender, body mass index (BMI), age, etc.), obesity-related parameters and pertinent laboratory tests including levels of HbA1C, FBS, SGOT, SGPT, T3, T4, TSH, creatinine, cholesterol, triglyceride, etc.

The aforementioned clinical chemistry analysis, including levels of creatinine, AST, ALT, FBS, HbA1c, etc., were measured at Farvardin Novin Medical Laboratory or other centers by the patients before (prior to surgery) and after surgery (checkup). Therefore, the researcher filed these data as supplementary information.

Two visits, viz. before surgery (visit 1) and 6 months after surgery (visit 2), were taken place at Farvardin Novin Medical Laboratory. The design of the visits for phenotyping were similar. Patients were required to abstain from caffeine and heavy physical exercise for at least 24 h and from grapefruit juice for at least 1 week before the study session. Each patient was administered a cocktail with 125 mL of water containing caffeine sachet after an overnight fast, and baseline blood sample was obtained thereafter. The next blood samples were collected at 1, 2, and 3 h after oral administration of the cocktail. Patients were given a standard meal after the last sampling. All collected samples were harvested and frozen at -70 ℃ until assayed.

Echocardiography was performed by one operator for all the patients at the division of echocardiography in Imam Khomeini hospital complex and the parameters related to stroke volume (SV) and cardiac output (CO) calculations including aortic annulus diameter, velocity–time integral of left ventricular outflow(LVOT-VTI), velocity–time integral of descending thoracic aorta(des-VTI) and the heart rate(HR) were measured. SV and CO measured with the following formula based on “continuity equation”:

$$\begin{array}{c}\mathrm{SV}=0.785*{\left(\mathrm{aortic},,\mathrm{annulus}\right)}^2*\mathrm{LVOT}-\mathrm{VTI}\\ \mathrm{CO}=\mathrm{SV}*\mathrm{HR}\end{array}$$

Moreover eye ball estimation of left ventricular ejection (LVEF) were documented per patient.

In the second phase with a similar design, obesity-related differences in metabolic enzyme activities were assessed compared to those of healthy non-obese control group, along with the possibility of returning CYP activities to normal levels as a result of bariatric surgery.

All of experimental procedures have been noted in Table 1.

Table 1.

Experimental procedures

Demographic data BMI calculations before & after surgery
Levels of pro-inflammatory cytokines: IL-1β & IL-6 Before & After Surgery
Levels of metabolic ratios for each probe Before & After Surgery at each sampling time (phenotyping)
Genotype analysis of CYP450s
Levels of clinical data such as FBS, ALT, AST, etc Before & After Surgery
Echocardiography parameters such as stroke volume (SV) and cardiac output (CO) Before & After Surgery

The results of this project will be submitted for publication in a peer-reviewed journal.

Study population

Totally, about 80 participants comprising a control group of non-obese healthy subjects (public) and morbidly obese individuals (patients) who were candidates for bariatric surgery (sleeve gastrectomy and gastric bypass) were enrolled in the study based on eligibility criteria and their medical history.

Written informed consent of all patients was obtained prior to the initiation of study procedure.

Public and patient selection

Healthy non-obese individuals were invited to participate in the study as a control group through various methods such as face-to-face communication by project researchers, an announcement on the college website or social media. Patients who visited the surgeon were scheduled based on clinical indications and then contacted by the project researcher via phone calls or in-person at the center. All volunteers interested in participation were informed of the objectives, risks, and inconveniences of the trial during the screening visit. In addition, they were provided with written information, contact details of the principal investigators, as well as copies of their signed consent/assent forms (the original copy was stored at the center) in compliance with Human Ethics guidelines. Moreover, medical history, alcohol drinking habits, nicotine use, menopausal status, concomitant drugs (including OTC drugs like omega-3, herbal medicines dietary supplements and similar substances), changes in physical activity and/or diet in the last 3 months, and comorbidities that might affect drug bioavailability were recorded during this appointment. The patients' BMIs were calculated as weight in kilograms divided by the square of the height in meters and was added to previous information as the chief inclusion criterion.

All interested participants were informed of their right to withdraw from the study at any time during the process, without any consequence for their future health care and without giving any reason for doing so. Immediate intervention or treatment is available in case of an acute adverse event, e.g., an anaphylactic reaction. The present protocol does not influence patient treatment procedures.

Sample size

According to the largest documented variance of CYPs activities in previous studies, at least 35 patients should be incorporated in each group to evaluate the changes in activities of CYPs with a power of 80% and an alpha value of 0.05 [5]. Considering the elimination of inter-individual differences with a two-armed design of the present protocol, it seems that the recruitment of the same number of subjects can also fulfill the objectives of this project. Due to the explorative nature of the study, an additional number of patients will be included in order to ensure relevant assessments of other outcome variables. With an anticipated dropout rate of 10%, approximately 40 volunteers per group (a total of 80 participants) may lead to enough power of the study.

Safety

Since all the probes administered in the cocktail are in sub-therapeutic doses, no serious adverse drug event was anticipated for the volunteers during and after the sessions. The cocktail administration may only entail a slight sedative pharmacological effect because of midazolam intake, while no other adverse events were observed in the subjects.

Gifts

A package consisting multi-vitamins, ferrous sulfate-folic acid, and calcium-citrate for a period of 5 months post-surgery was prepared for the volunteers on their 1-month check-up visit after operation.

Inclusion and Exclusion Criteria

Healthy adolescent volunteers (with a BMI < 25) and morbidly obese patients who are candidates for bariatric surgery (defined here with a BMI ≥ 40) aged between 18 and 60 years, HbA1C < 6.5%, without a recent history of hospitalization over the past 12 months will be recruited here. The subjects should not have any known history of metabolic diseases, such as diabetes. All the recruited participants (healthy or obese) should not have uncontrolled thyroid problems, cirrhosis, IBD, Helicobacter pylori infection, and any infectious disease (active or in the last 4 weeks). Other inclusion criteria for all volunteers will be being non-smoker (for at least 2 months prior to the study) and being non-alcohol abuser.

The subjects who are taking medication known to alter metabolism activity such as corticosteroids, or NSAIDs that administered with the purpose of anti-inflammatory effects will be excluded from this trial.

Women will be excluded if they are pregnant or in their breastfeeding stage and will be asked about having a regular menstrual cycle.

Exclusion criteria were as follows: those usually treated with drugs with inhibitory or inducing effect on DMEs which their substrates are used in the phenotyping cocktail, and patients with a history of hypersensitivity to drugs used in the cocktail. Subjects who underwent an organ transplant surgery or patients with an active cancer, and having an estimated glomerular filtration rate (GFR) of < 50 mL/min/1.73 m².

Participant flow and follow-up

From a group of 90 interviewed patients, 51 persons were not eligible (not meeting incl./excl. criteria, n = 21; declined to participate, n = 23; other reasons, n = 7) and 39 volunteers participated in the study, consisting of five men and 34 women, with a mean age of 39 (19–59) years and a mean BMI of 46.5 (38.9–54.1) kg/m². None of the participants used medication that interacted with the drug metabolism pathways evaluated by the cocktail during all test periods. Sixteen subjects successfully completed both the study sessions (others: three persons declined to undergo surgery, one woman was rejected after cardiac check-up, 2 women could not afford the costs, 3 women lost the second visit because of influenza, etc., and the remaining 14 subjects did not catch the final session time-point. Six months after surgery (visit 2), the average of total weight loss was 26.9%. All biological parameters, especially liver transaminases, improved after surgery.

Experimental protocol

After the inclusion of obese patients and the public, admitted participants were invited to the laboratory. On an experimental day and after an overnight fasting, volunteers were subjected to a 3-h PK cocktail investigation. All the cocktail capsules were prepared at the pharmaceutical lab of the Pharmacy Faculty under GLP conditions.

Each patient received one cocktail capsule (with the aforementioned composition) with a cup of coffee (caffeine: 100 mg) and remained fasting until the last time-point collection. Four blood samples were drawn via venous catheters immediately before (time 0) and at 1, 2, and 3 h after the capsule administration. Immediately after collection, blood samples were centrifuged at 4 °C and aliquots were then stored at -80 °C until analysis. Before aliquoting plasma samples for phenotype measurements, two additional plasma samples were separated and sent to the laboratory for inflammatory marker measurements. Besides the aforementioned samples, a separate sample of the whole blood was obtained and transferred to special vacutainers, which is preferably an EDTA or sodium citrate tube for genotype measurements because it has been demonstrated that PCR is partly inhibited by heparin [16]. Participants were discharged after the 3-h sample collection and taking echocardiogram tests.

After the first session of cocktail investigation, obese patients underwent bariatric surgery with a 6-month follow-up period under the supervision of their physician. During this period, patients were monitored and motivated by the project researcher for following their regimen besides using their prescribed drugs and gifted supplements. The weight of patients was recorded every month, and cocktail administration and all covariate measurements were repeated at the end of this period. The healthy volunteers will not undergo further cocktail investigations or follow-ups.

Time schedule

• Inclusion of the first patient: 30 April 2019.

• Inclusion of the last patient: -

• Recruitment time: approximately 1.5 year.

• Follow-up: up to 6 months for each patient from the date of surgery.

• End of study: LPLV, approximately 2 years after the study start.

• (1 year after the last patient inclusion).

Laboratory methods

Phenotype assessment

Utilization of our probe drug cocktail enables us to characterize the effect of obesity on the metabolism of drugs by targeting specific activity of different CYP450 isoforms. Each of our probe drugs is selective for an isoform of the CYP450s being free of interaction with one another. Phenotypic indexes were determined as previously validated using metabolic ratios (MRs) of plasmatic concentrations. The cocktail probes and their corresponding CYP-specific metabolites will be quantified in plasma using the high-performance liquid chromatography/tandem mass spectrometry method, which was previously fully validated by Bosilkovska et al. [17].

Determination of pro-inflammatory cytokine levels

Levels of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) will be quantified by electrochemiluminescence immunoassays using the V-PLEX Pro-inflammatory Panel 1 Human Kit, QuickPlex SQ120 Imager, and the WORKBENCH software (MSD, Rockville, MD).

Genotype analysis of CYP450s

Genomic DNA was extracted from whole blood samples in both groups (patients and public) throughout the study. DNA samples will be used for genetic analyses associated with the mentioned CYP450s using semi-quantitative RT-PCR or other appropriate methods [17, 18].

Data analysis

Pharmacokinetic parameters will be estimated using non-compartmental methods by Excel version 6.2.1. Single-point MRs will be determined as the concentration ratio between the metabolite and the administered probe substrate at different time points. The MRs at the steps of controlling pre-post patients and patient-healthy volunteers will be compared using a non-parametric Wilcoxon signed-rank test. Simple and multiple linear regressions will be applied to assess correlations between MRs and pro-inflammatory cytokines, as well as other clinical variables. All statistical analyses will be determined using SPSS software version 21 (Chicago, IL). P values ≤ 0.05 will be considered statistically significant.

Strengths and limitations of this study

Strengths

• Sampling in a short period (3 h).

• Analyzing the impacts of different types of surgery on the important CYP450 enzyme activity.

• Evaluating the relationship between inflammatory cytokine levels and important CYP450 enzyme activity.

• Omitting inter-individual variations.

• Evaluating important CYP450 enzyme genotypes in the patients to ensure that the changes in CYP450 enzyme activity are due to obesity and not genetic polymorphisms.

Limitations

• Following up patients for six months.

• Dificulties in finding non-diabetic obese patients who are candidates for bariatric surgery

Data management

In the designed plan, all participants will be coded by a related identification number in order to respect their privacy. Only the researchers will have access to subjects’ identities and numbers. All documents related to the study will be kept in locked files while being analyzed in a non-nominal manner. DNA samples will merely be applied for genetic analyses associated with CYP450s or other enzymes/transporters of drugs relevant for obesity, associated comorbidities, and drug response variability. The samples will not be used to disentangle other complicated situations except the present study.

Discussion

A number of implications derive from phenoconversion, which occur due to co-medications and comorbidities. For this reason, genotype of a patient exhibits only a part of the evidence needed to suggest “the appropriate drug at the right dose for the first time”. Even with definite and convincing data correlating patients’ genotype with clinical outcome(s), there are barriers in translating these data clinically into practical information with respect to pharmacotherapy and relevant drug interactions. A matter that would need to be taken into consideration in the future encompasses distinguishing (a) drugs that are susceptible to phenoconversion, (b) co-medications that can lead to phenoconversion, and (c) dosage adjustments that need to be applied during and following phenoconversion. Concentrating on these issues requires further investigations [19].

The cocktail approach suggests a safe, valuable, and effective tool for screening and/or drug metabolism phenotyping in humans, with an impressive utilization in toxicological and clinical studies. Thus, a research based on both genotyping and in vivo phenotyping approaches will enhance the quality of data gathered to optimize researches on drug metabolism and drug interaction. Further examination on simultaneous genotyping and phenotyping in both healthy individuals and patients would produce useful information regarding intra- and inter-individual variations in drug metabolism, with direct impacts on personalized medicine [20].

The phenomenology, clinical results, and basic mechanisms of the impacts of inflammation on the regulation of CYP450 and drug transporters have been illustrated through different studies. Inter- and intra-individual variations in the activity of cytochromes P450, and particularly drug transporters because of inflammation, have critical implications for the administration of many drugs in various clinical settings. Although several inflammatory cytokines can regulate these genes and proteins, the role of IL-6 in the regulation of both P450 enzymes and transporters was considerable in all models. Furthermore, various mechanisms have been discovered for the impacts of inflammation on regulating the expression of CYP enzymes and transporters versus the basal state in this regard [21].

The prevalence of obesity has increased by 400% in the last two decades and continues to rise. Therefore, overweight and obesity may soon become one of the most serious reasons for poor health. Obesity causes many challenges for adjusting optimal therapeutic doses of drugs. Obesity results in changes in some pathophysiological agents including variations in regional blood flow, hormonal release, cardiac output, balance of adipose tissue versus muscle tissue, and the expression of pro-inflammatory cytokines. These pathophysiological conditions can lead to changes in the pharmacokinetics of medications prescribed for the treatment of obesity-related comorbidities and necessitate dose adjustments in these patients. Since obese patients usually receive multidrug therapy, this could be taken as a pertinent concern. The main strategies for the treatment of morbidly obese patients include i) diet and physical exercise, ii) medications, and iii) bariatric surgery. The maintenance of weight loss through dietary management is very challenging because it involves permanent changes in eating habits. Orlistat is one of the medications with the approval of long-term use, which is currently available; nevertheless, it has its own disadvantages, such as poor average amount of weight loss and uncomfortable gastrointestinal side effects. The most practical approach for weight loss, especially in morbid obesity, is bariatric surgery, which is operated using a variety of techniques [22].

Abdominal or visceral obesity can lead to high levels of most pro-inflammatory cytokines and adipokines, such as IL-6, TNF-α, and leptin, which have previously been related to reductions in the expression of DMEs and transporters [23–26]. For many medications, the activities of DMEs and transporters are essential for their appropriate therapeutic response [18]. The current study principally designed a within-subject comparison to demonstrate whether or not a significant decrease in weight, induced by bariatric surgery, could modulate the phenotype of major CYPs in obese patients. Additionally, different types of surgeries will be compared to evaluate differences in CYP activities before and after bariatric surgery in morbidly obese patients. Besides, healthy participants will be evaluated as a control group.

Declarations

Ethics and dissemination

Approval (ID: IR.TUMS.TIPS.REC.1397.104) was obtained from the Ethics Review Board of Tehran University of Medical Sciences (Tehran, Iran).

Conflict of interest

The authors have no commercial associations that might be a conflict of interest in relation to this article.