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Effect of Sleeve Gastrectomy on Buprenorphine Pharmacokinetics: A Planned Case Observation

  • Hege-Merete Krabseth
    Correspondence
    Address correspondence to: Hege-Merete Krabseth, MD, Professor Brochs gate 6, 7030, Trondheim, Norway.
    Affiliations
    Department of Clinical Pharmacology, Clinic of Laboratory Medicine, St. Olav University Hospital, Trondheim, Norway
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  • Magnus Strømmen
    Affiliations
    Centre for Obesity Research, Clinic of Surgery, St. Olav University Hospital, Trondheim, Norway

    Department of Clinical and Molecular Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
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  • Olav Spigset
    Affiliations
    Department of Clinical Pharmacology, Clinic of Laboratory Medicine, St. Olav University Hospital, Trondheim, Norway

    Department of Clinical and Molecular Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
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  • Arne Helland
    Affiliations
    Department of Clinical Pharmacology, Clinic of Laboratory Medicine, St. Olav University Hospital, Trondheim, Norway

    Department of Clinical and Molecular Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
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Open AccessPublished:September 25, 2020DOI:https://doi.org/10.1016/j.clinthera.2020.08.016

      Abstract

      Purpose

      Bariatric surgery may affect the absorption and metabolism of drugs by various mechanisms. We present a planned case observation of a patient treated with sublingual buprenorphine in an opioid maintenance treatment program, and the observed changes in buprenorphine pharmacokinetics following gastric sleeve surgery.

      Methods

      Serial blood samples during a dose interval of 24 hours were obtained approximately 1 year preoperatively as well as 1 week, 1 month and 12 months postoperatively and key pharmacokinetic variables were calculated.

      Findings

      The systemic exposure of buprenorphine (AUC) was relatively stable from the preoperative sampling to 1 week postoperatively (−6.3%), but declined markedly at 1 month (−43%) and 12 months (−42%) postoperatively. The maximum concentration of buprenorphine almost doubled at 1 week postoperatively before returning to baseline values 1 month and 12 months postoperatively.

      Implications

      This case observation indicates that after sleeve gastrectomy, the systemic exposure of sublingual buprenorphine can decrease. Clinicians should be aware of the possibility of loss of effect and emerging abstinence symptoms following sleeve gastrectomy. We recommend monitoring the patient closely for abstinence symptoms postoperatively and considering measuring serum concentrations of buprenorphine pre- and postoperatively.

      Key words

      Introduction

      Obesity is a major health risk, and bariatric surgery has proven to be an effective method to reduce body weight.
      • Colquitt J.L.
      • Pickett K.
      • Loveman E.
      • Frampton G.K.
      Surgery for weight loss in adults.
      The demand for such treatment is rising, and there were nearly 700,000 bariatric procedures performed worldwide in 2016. The sleeve gastrectomy constituted more than one half of these procedures.
      • Angrisani L.
      • Santonicola A.
      • Iovino P.
      • et al.
      IFSO Worldwide Survey 2016: primary, endoluminal, and revisional procedures.
      TablePharmacokinetic variables based on the concentrations of buprenorphine in a woman undergoing bariatric surgery with sleeve gastrectomy.
      VariablePreoperatively (Baseline)1 Week Postoperatively1 Month Postoperatively12 Months Postoperatively
      C0, nmol/L3.12.41.91.2
      Cmax, nmol/L11.220.78.110.0
      Tmax, h0.800.500.501.0
      AUC0–24, nmol/L × h1131056465
      AUC0–24, % decrease
      Compared with AUC0–24 preoperatively.
      06.34342
      CL/F, mL/min634167651116710913
      C0 = trough concentration (measured immediately before intake of the daily dose of buprenorphine); Cmax = maximum concentration; tmax = time from dose intake to Cmax; AUC0-24 = area under the concentration-time curve from 0 to 24 hours after dose intake; CL/F = apparent sublingual clearance.
      Compared with AUC0–24 preoperatively.
      Existing guidelines provide few recommendations in the case of opioid maintenance therapy.
      • Mechanick J.I.
      • Apovian C.
      • Brethauer S.
      • et al.
      Clinical practice guidelines for the perioperative nutrition, metabolic, and nonsurgical support of patients undergoing bariatric procedures—2019 update: cosponsored by American association of clinical endocrinologists/American college of endocrinology, the obesity society, American society for metabolic & bariatric surgery, obesity medicine association, and American society of anesthesiologists—executive summary.
      Opioid agonists play an important role in the recovery process after opioid addiction, a process that may take several years. Occasionally, patients on opioid maintenance therapy are referred for bariatric surgery. Even after a mental health evaluation, clinicians may be reluctant to operate on such patients due to the unknown effects of bariatric surgery on the pharmacology of opioid agonists. The lack of research on bioavailability of medications after bariatric surgery adds to the risk of treatment refusal for patients on opioid maintenance therapy. To our knowledge, the only publication so far on opioid agonists and bariatric surgery is a case observation of the absorption of methadone in a patient undergoing sleeve gastrectomy.
      • Strømmen M.
      • Helland A.
      • Kulseng B.
      • Spigset O.
      Bioavailability of methadone after sleeve gastrectomy: a planned case observation.
      A review concluded that a history of substance abuse is not associated with less weight loss after bariatric surgery.
      • Kanji S.
      • Wong E.
      • Akioyamen L.
      • Melamed O.
      • Taylor V.H.
      Exploring pre-surgery and post-surgery substance use disorder and alcohol use disorder in bariatric surgery: a qualitative scoping review.
      By having recovered from substance abuse in the first place, the patient may possess resources for behavioral change that could also be relevant for weight loss maintenance. Although patients receiving opioid maintenance therapy have not necessarily recovered from the substance use problem, participating in a maintenance program may involve being surrounded by a supportive network, which may also be beneficial for the surgical outcome.
      Buprenorphine is a semi-synthetic opioid derived from thebaine, a naturally occurring alkaloid of the opium poppy (Papaver somniferum). Buprenorphine is used clinically as an analgesic and as substitution treatment for opioid dependence.
      • Elkader A.
      • Sproule B.
      Buprenorphine: clinical pharmacokinetics in the treatment of opioid dependence.
      The effects of buprenorphine, mainly mediated through opioid mu receptor agonism, are similar to the effects of other opioids, including analgesia, sedation, euphoria, and respiratory depression. Being a partial agonist, its maximum opioid effects are weaker than those of a full agonist, providing a wider safety margin. Buprenorphine is extensively metabolized through N-dealkylation to the less pharmacologically active metabolite norbuprenorphine. The N-dealkylation is mainly mediated by cytochrome P-450 (CYP) 3A4. In addition, both buprenorphine and norbuprenorphine undergo glucuronidation. There is a considerable variation in the reported terminal t½ for buprenorphine, with mean values ranging from 3 to 44 h.
      • Elkader A.
      • Sproule B.
      Buprenorphine: clinical pharmacokinetics in the treatment of opioid dependence.
      Gastric pH, gastric emptying time, gastrointestinal transit time, and presystemic metabolic effects of enzymes in the gut mucosa may change after bariatric surgery.
      • Azran C.
      • Wolk O.
      • Zur M.
      • et al.
      Oral drug therapy following bariatric surgery: an overview of fundamentals, literature and clinical recommendations.
      ,
      • Angeles P.C.
      • Robertsen I.
      • Seeberg L.T.
      • et al.
      The influence of bariatric surgery on oral drug bioavailability in patients with obesity: a systematic review.
      Bariatric surgery might also affect drug solubility and the absorptive area of the drug in the gastrointestinal tract.
      • Miller A.D.
      • Smith K.M.
      Medication and nutrient administration considerations after bariatric surgery.
      These factors may alter the pharmacokinetic variables of medicines taken orally after surgery. Buprenorphine, however, is administered sublingually and is absorbed by the oral mucosa when used as substitution therapy, thereby largely bypassing the gastrointestinal tract and presystemic metabolism. Such drugs should therefore, at least in theory, be less affected by bariatric surgery than drugs taken orally.
      To our knowledge, the effects of bariatric surgery on the pharmacokinetic variables of buprenorphine have not been studied previously. We present here a planned case observation in a patient treated with buprenorphine in an opioid maintenance treatment program, and the observed changes in buprenorphine pharmacokinetic variables.

      Case Description

      A 45-year-old woman with a history of illicit drug abuse was referred for bariatric surgery at a Norwegian university hospital. She had been injecting heroin for 9 years before starting opioid maintenance treatment. The last 5 years she had been treated with sublingual buprenorphine, with a constant dose of 20 mg/d, in a combination tablet with naloxone 5 mg/d. At the time of referral she weighed 116 kg (corresponding to a body mass index [BMI] of 42.0 kg/m2) and had ankle arthrosis. Her surgical history involved a previous laparoscopic cholecystectomy. Except for buprenorphine/naloxone 20/5 mg/d, she used no medications regularly.
      The patient underwent a psychiatric evaluation as part of the multidisciplinary preoperative screening in the Obesity Clinic. She was informed about the lack of evidence concerning the potential influence of bariatric surgery on the pharmacology of buprenorphine and was invited to participate in a pharmacokinetic study. The study is part of a pharmacokinetic platform study, Changes in oral health and pharmacokinetics of drugs after bariatric surgery, BAR-MEDS, which is approved by the Regional Committee for Medical and Health Research Ethics in Mid Norway (ref. 2016/1145).
      The patient participated in a group-based preoperative preparation program. During this preoperative period, including the last 3 weeks following a liquid very-low-calorie diet, she lost 15 kg before surgery (new BMI, 37.1 kg/m2). She underwent laparoscopic sleeve gastrectomy under general anesthesia with no perioperative complications. She thereafter returned to her regular dosage of buprenorphine 20 mg/d with the addition of naloxone as previously. Other medications were enoxaparin 40 mg/d subcutaneously the first 3 weeks and paracetamol as needed for pain.
      The patient had a successful weight loss, weighing 98 kg (BMI, 36.0 kg/m2) one week after the operation, 94 kg (BMI 34.0 kg/m2) after one month, and 64 kg (BMI 23.8 kg/m2) twelve months after surgery. Total body fat measured by bioelectrical impedance was reduced from 58.7 kg before surgery to 16.9 kg twelve months after the operation. Three years after surgery, her body weight was 68 kg (BMI, 25.0 kg/m2). She described her physical functioning and quality of life as considerably improved. However, her ankle arthrosis still caused pain and she developed osteoporosis, for which she was treated with intravenous zoledronic acid. She also developed heartburn after the surgery, which was treated with pantoprazole 20 mg/d.
      The buprenorphine dose was ingested every morning and remained unchanged at 20 mg/d during the first 12 postoperative months. One week after surgery, the patient reported less effect of the medication in the evening and at night. At both 1 and 12 months postoperatively, she reported feeling anxious, having chills and sweats, and experiencing interrupted sleep at night. She perceived these symptoms as opioid abstinence.
      Serial blood samples were obtained ~1 year preoperatively, as well as 1 week, 1 month, and 12 months postoperatively. Sampling took place at 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 12, and 24 h after buprenorphine ingestion. Due to difficulty with peripheral venous access, samples at 3, 3.5, and 4 h were missing from series 1 week postoperatively. Buprenorphine was analyzed with an LC-MS method developed at our laboratory.
      • Stallvik M.
      • Nordstrand B.
      • Kristensen Ø.
      • Bathen J.
      • Skogvoll E.
      • Spigset O.
      Corrected QT interval during treatment with methadone and buprenorphine—relation to doses and serum concentrations.
      In brief, 1.0 mL serum, 50 μL internal standard (d4-buprenorphine), and 2.0 mL ammonium carbonate were mixed and applied onto a preconditioned solid-phase extraction column (Varian Bond Elute C18; Varian, Palo Alto, California). After elution with buffer, evaporation, and reconstitution, the samples were injected on an Agilent MSD 1100 LC-MS system (Agilent, Palo Alto, California). Separation was performed on a Zorbax SB-CN 4.6 mm × 150 mm column (Agilent) with a mobile phase consisting of methanol/formate/ammonium acetate (90/5/5). Buprenorphine was monitored at m/z 450.3, 451.3, and 418.3, and d4-buprenorphine at m/z 454.3. The limit of quantification was 0.5 nmol/L, and the method was linear at least up to 50 nmol/L. Between-day %CVs calculated from these samples were <3.9% at 1 nmol/L and 3.5% at 10 nmol/L.
      Key pharmacokinetic variables were calculated by means of the pharmacokinetic software Kinetica version 4.3. The patient was genotyped for the CYP enzyme variants CYP3A4∗22 and CYP3A5∗3, both of which cause reduced enzyme activity.

      Results

      The time–concentration curves of buprenorphine are presented in the Figure, and key pharmacokinetic data are presented in the Table. The systemic exposure of buprenorphine, expressed by the AUC, was relatively stable from the preoperative sampling to 1 week postoperatively (−6.3%) but declined markedly at 1 month (−43%) and 12 months (−42%) postoperatively. Correspondingly, buprenorphine clearance was higher at 1 and 12 months postoperatively than at baseline. The Cmax of buprenorphine almost doubled at 1 week postoperatively before returning to approximate baseline values 1 and 12 months postoperatively.
      Figure 1
      FigureSerum concentrations of buprenorphine in a patient undergoing sleeve gastrectomy.
      Genotyping revealed that the patient had genotypes CYP3A4∗1/∗1 and CYP3A5∗3/∗3.

      Discussion

      In this planned case observation, we observed a change in the pharmacokinetic variables of buprenorphine, with a marked decrease in drug exposure 1 and 12 months after sleeve gastrectomy, and an increase in Cmax 1 week after surgery.
      Buprenorphine administered orally undergoes extensive first-pass metabolism, causing a very low oral bioavailability. When administered sublingually, nonionized buprenorphine is absorbed into the systemic circulation from the sublingual area,
      • Elkader A.
      • Sproule B.
      Buprenorphine: clinical pharmacokinetics in the treatment of opioid dependence.
      thus bypassing the gut, the portal system and the liver. Buprenorphine bioavailability by the sublingual route has been estimated to be ~50% but is subject to large interindividual variability.
      • Kuhlman Jr., J.J.
      • Lalani S.
      • Magluilo Jr., J.
      • Levine B.
      • Darwin W.D.
      Human pharmacokinetics of intravenous, sublingual, and buccal buprenorphine.
      Buprenorphine is a weak base (pKa 8.24).
      • Mendelson J.
      • Upton R.A.
      • Everhart E.T.
      • Jacob 3rd, P.
      • Jones R.T.
      Bioavailability of sublingual buprenorphine.
      Changes in salivary pH may alter its absorption by affecting the degree of ionization.
      • Elkader A.
      • Sproule B.
      Buprenorphine: clinical pharmacokinetics in the treatment of opioid dependence.
      ,
      • Mendelson J.
      • Upton R.A.
      • Everhart E.T.
      • Jacob 3rd, P.
      • Jones R.T.
      Bioavailability of sublingual buprenorphine.
      Bariatric surgery is associated with an increased risk of gastroesophageal reflux, which may decrease oral pH.
      • Heling I.
      • Sgan-Cohen H.D.
      • Itzhaki M.
      • Beglaibter N.
      • Avrutis O.
      • Gimmon Z.
      Dental complications following gastric restrictive bariatric surgery.
      Moreover, chronic use of opioid mu receptor agonists such as buprenorphine leads to sweet taste preference.
      • Mysels D.J.
      • Sullivan M.A.
      The relationship between opioid and sugar intake: review of evidence and clinical applications.
      When bacteria in the oral cavity metabolize carbohydrates, acidic products are released.
      • Hans R.
      • Thomas S.
      • Garla B.
      • Dagli R.J.
      • Hans M.K.
      Effect of various sugary beverages on salivary pH, flow rate, and oral clearance rate amongst adults.
      At physiological pH, buprenorphine exists in both ionized and nonionized forms. With decreased oral pH, a higher proportion of the drug will be ionized, thereby reducing its absorption and causing lower serum concentrations. In addition, patients who undergo bariatric surgery could possibly experience a reduction in saliva production as well as dry mouth, which could lead to reduced absorption of sublingual buprenorphine.
      Buprenorphine undergoes hydroxylation via hepatic CYP3A4 and CYP3A5 to norbuprenorphine. The patient did not use any medication known to interfere with CYP3A metabolism during the study period. Genotyping showed that the patient had the CYP3A4∗1/∗1 genotype, signifying normal metabolic capacity via this enzyme, and the CYP3A5∗3/∗3 genotype, which encodes a nonfunctional enzyme and is very common in white populations. Obesity is associated with low-grade inflammation in the adipose tissue, which leads to secretion of inflammatory cytokines, chemokines, and adipokines. This may lead to reduced activity of CYP enzymes.
      • Rao S.R.
      Inflammatory markers and bariatric surgery: a meta-analysis, Inflammation research.
      CYP3A activity has been shown to be inversely correlated with body weight.
      • Brill M.J.
      • Diepstraten J.
      • van Rongen A.
      • van Kralingen S.
      • van den Anker J.N.
      • Knibbe C.A.
      Impact of obesity on drug metabolism and elimination in adults and children.
      Following bariatric surgery, it has been suggested that hepatic CYP3A activity increases to a new steady-state level within 1 year.
      • Angeles P.C.
      • Robertsen I.
      • Seeberg L.T.
      • et al.
      The influence of bariatric surgery on oral drug bioavailability in patients with obesity: a systematic review.
      This factor could thus, at least in part, explain the increased clearance observed 12 months after surgery but probably not the increased clearance 1 month after surgery.
      Buprenorphine is highly protein bound, primarily to alpha- and beta-globulins,
      • Elkader A.
      • Sproule B.
      Buprenorphine: clinical pharmacokinetics in the treatment of opioid dependence.
      of which the acute-phase protein orosomucoid (α1-acid glycoprotein) is the most important. A decreased concentration of these proteins after weight loss could theoretically lead to a lower total concentration of buprenorphine with an unchanged free (unbound) concentration. However, because the changes in the orosomucoid concentration were relatively small and the concentrations were within the reference range, with a peak 1 week after surgery as expected, these alterations cannot explain the relatively extensive long-term changes seen for buprenorphine in this patient.
      A potential reduction in the volume of distribution associated with weight loss may increase the concentration of a drug after the first dose and may also increase the peak concentration and reduce the elimination half-life at steady state; however, it generally has a negligible influence on AUC at steady state. Frequent diarrhea after surgery could reduce the enterohepatic recirculation of buprenorphine, potentially increasing drug elimination in feces. However, the patient did not experience diarrhea during the study period. Nausea and reduced mobility could occur after surgery and may influence the absorption of drugs. This is, however, of minor importance for drugs taken sublingually. Moreover, the patient was rapidly mobilized after the surgery, and she did not report nausea. Finally, it should be mentioned that the patient's renal function did not change during the study period.
      Buprenorphine concentrations at t = 0 h and t = 24 h were similar in all 4 test days, which may be seen as an indication of adequate medication adherence. Because the patient had been taking buprenorphine for many years, we consider that erroneous administration (swallowing, chewing, or short hold time of the tablet in the oral cavity) is less likely. It is therefore probable that the observed changes are caused by pharmacokinetic alterations following bariatric surgery and weight loss, although the changes seem to be more extensive than what would be expected solely from the mechanisms discussed here.

      Conclusions

      The present case observation indicates that after sleeve gastrectomy, the systemic exposure of sublingual buprenorphine can decrease. The mechanism could be lower bioavailability due to decreased oral pH and/or increased metabolism via CYP3A. Clinicians should be aware of the possibility of loss of effect and emerging abstinence symptoms following sleeve gastrectomy. We recommend monitoring the patient closely for abstinence symptoms postoperatively and considering the measurement of serum concentrations of buprenorphine preoperatively and postoperatively.
      It should be emphasized that our observations are based on a single case only and should be interpreted with caution. Further research is needed to obtain more knowledge about the effect of sleeve gastrectomy on buprenorphine pharmacokinetic variables. In particular, studies with physiologically based pharmacokinetic modeling would be of interest to further elucidate the underlying mechanisms of the observed changes.

      Disclosures

      The authors have indicated that they have no conflicts of interest regarding the content of this article.

      Acknowledgments

      The authors are grateful to the FFU, The Joint Research Committee, at St. Olav University Hospital and the Faculty of Medicine, Norwegian University of Science and Technology , for funding the project. The authors also thank the devoted study nurses at the Centre for Obesity Research, St. Olav University Hospital, for their contribution.
      The authors contributed to the paper as follows: Dr. Spigset, Dr. Helland, and Mr. Strømmen conceptualized the study; Mr. Strømmen obtained the data; and Drs. Spigset, Helland, and Krabseth were responsible for analyses and visualizations. The manuscript was drafted by Dr. Krabseth, and Dr. Spigset, Dr. Helland, and Mr. Strømmen were involved in its editing. All authors approved the final version of the manuscript.

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