Impact of body weight, low energy diet and gastric bypass on drug bioavailability, cardiovascular risk factors and metabolic biomarkers: protocol for an open, non-randomised, three-armed single centre study (COCKTAIL)

Hjelmesæth, Jøran; Åsberg, Anders; Andersson, Shalini; Sandbu, Rune; Robertsen, Ida; Johnson, Line Kristin; Angeles, Philip Carlo; Hertel, Jens Kristoffer; Skovlund, Eva; Heijer, Maria; Ek, Anna-Lena; Krogstad, Veronica; Karlsen, Tor-Ivar; Christensen, Hege; Andersson, Tommy; Karlsson, Cecilia

doi:10.1136/bmjopen-2018-021878

Cited by 21 publications

(22 citation statements)

References 69 publications

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“…For liver, true‐cut biopsies were obtained from parenchyma close to the edge of the right liver lobule. Biopsies were snap frozen in liquid nitrogen directly upon sampling and stored at −80°C until analysis 22 …”

Section: Methodsmentioning

confidence: 99%

“…In this study, we quantified the global proteomes of matched whole lysate jejunum and liver obtained from 37 donors undergoing gastric bypass surgery. These patients were enrolled in the COCKTAIL (Impact of Body Weight and Weight Loss on Drug Bioavailability, Cardiovascular Risk Factors and Metabolic Biomarkers) study 22 . A primary objective in COCKTAIL was to investigate the relationship between body composition and jejunum and liver protein expression and activity of proteins involved in the absorption, distribution, metabolism, and excretion (ADME) of drugs.…”

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confidence: 99%

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Drug Disposition Protein Quantification in Matched Human Jejunum and Liver From Donors With Obesity

Wegler

Wiśniewski

Robertsen

et al. 2022

Clin Pharma and Therapeutics

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Mathematical models, such as physiologically‐based pharmacokinetic models, are used to predict, for example, drug disposition and toxicity. However, populations differ in the abundance of proteins involved in these processes. To improve the building and refinement of such models, they must take into account these interindividual variabilities. In this study, we used global proteomics to characterize the protein composition of jejunum and liver from 37 donors with obesity enrolled in the COCKTAIL study. Liver protein levels from the 37 donors were further compared with those from donors without obesity. We quantified thousands of proteins and could present the expression of several drug‐metabolizing enzymes, for the first time, in jejunum, many of which belong to the cytochrome P450 (CYP) (e.g., CYP2U1) and the amine oxidase (flavin‐containing) (e.g., monoamine oxidase A (MAOA)) families. Although we show that many metabolizing enzymes had greater expression in liver, others had higher expression in jejunum (such as, MAOA and CES2), indicating the role of the small intestine in extrahepatic drug metabolism. We further show that proteins involved in drug disposition are not correlated in the two donor‐matched tissues. These proteins also do not correlate with physiological factors such as body mass index, age, and inflammation status in either tissue. Furthermore, the majority of these proteins are not differently expressed in donors with or without obesity. Nonetheless, interindividual differences were considerable, with implications for personalized prediction models and systems pharmacology.

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Drug Disposition Protein Quantification in Matched Human Jejunum and Liver From Donors With Obesity

Wegler

Wiśniewski

Robertsen

et al. 2022

Clin Pharma and Therapeutics

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“…The COCKTAIL study, a non-randomised, single-centre, 3-armed study, was carried out at the Morbid Obesity Centre, Vestfold Hospital Trust, Norway [ 22 ]. Patients with severe obesity (BMI ≥ 35 kg/m 2 in combination with comorbidity or BMI ≥ 40 kg/m 2 ) scheduled for elective weight-reducing intervention by either RYGB or strict diet were eligible for inclusion.…”

Section: Methodsmentioning

confidence: 99%

“…Patients with severe obesity (BMI ≥ 35 kg/m 2 in combination with comorbidity or BMI ≥ 40 kg/m 2 ) scheduled for elective weight-reducing intervention by either RYGB or strict diet were eligible for inclusion. The inclusion and exclusion criteria are fully described in the protocol paper [ 22 ]. Additionally, normal-to-overweight (BMI 18.5–29.9 kg/m 2 ) individuals scheduled for cholecystectomy were included as a cross-sectional control group.…”

Section: Methodsmentioning

confidence: 99%

“…The patient flow in the study has been described previously [ 20 ], and is further detailed in Figure S1. Both the RYGB group and the diet group were prescribed an initial 3-week low-energy diet (LED; < 1200 kcal/day), followed by additional 6 weeks of strict caloric restriction (< 800 kcal/day) induced by surgery or a very-low energy diet (VLED), respectively, in order to obtain a similar weight loss between the two groups [ 22 ]. All patients were prospectively followed for 2 years.…”

Section: Methodsmentioning

confidence: 99%

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Neither Gastric Bypass Surgery Nor Diet-Induced Weight-Loss Affect OATP1B1 Activity as Measured by Rosuvastatin Oral Clearance

et al. 2023

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Introduction Rosuvastatin pharmacokinetics is mainly dependent on the activity of hepatic uptake transporter OATP1B1. In this study, we aimed to investigate and disentangle the effect of Roux-en-Y gastric bypass (RYGB) and weight loss on oral clearance (CL/F) of rosuvastatin as a measure of OATP1B1-activity. Methods Patients with severe obesity preparing for RYGB ( n = 40) or diet-induced weight loss ( n = 40) were included and followed for 2 years, with four 24-hour pharmacokinetic investigations. Both groups underwent a 3-week low-energy diet (LED; < 1200 kcal/day), followed by RYGB or a 6-week very-low-energy diet (VLED; < 800 kcal/day). Results A total of 80 patients were included in the RYGB group (40 patients) and diet-group (40 patients). The weight loss was similar between the groups following LED and RYGB. The LED induced a similar (mean [95% CI]) decrease in CL/F in both intervention groups (RYGB: 16% [0, 31], diet: 23% [8, 38]), but neither induced VLED resulted in any further changes in CL/F. At Year 2, CL/F had increased by 21% from baseline in the RYGB group, while it was unaltered in the diet group. Patients expressing the reduced function SLCO1B1 variants (c.521TC/CC) showed similar changes in CL/F over time compared with patients expressing the wild-type variant. Conclusions Neither body weight, weight loss nor RYGB per se seem to affect OATP1B1 activity to a clinically relevant degree. Overall, the observed changes in rosuvastatin pharmacokinetics were minor, and unlikely to be of clinical relevance. Supplementary Information The online version contains supplementary material available at 10.1007/s40262-023-01235-5.

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Gastric Bypass vs Diet and Cardiovascular Risk Factors

Karlsson,

Johnson,

Greasley

et al. 2024

JAMA Surg

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ImportanceRoux-en-Y gastric bypass (RYGB) is associated with reduced cardiovascular (CV) risk factors, morbidity, and mortality. Whether these effects are specifically induced by the surgical procedure or the weight loss is unclear.ObjectiveTo compare 6-week changes in CV risk factors in patients with obesity undergoing matching caloric restriction and weight loss by RYGB or a very low-energy diet (VLED).Design, Setting, and ParticipantsThis nonrandomized controlled study (Impact of Body Weight, Low Calorie Diet, and Gastric Bypass on Drug Bioavailability, Cardiovascular Risk Factors, and Metabolic Biomarkers [COCKTAIL]) was conducted at a tertiary care obesity center in Norway. Participants were individuals with severe obesity preparing for RYGB or a VLED. Recruitment began February 26, 2015; the first patient visit was on March 18, 2015, and the last patient visit (9-week follow-up) was on August 9, 2017. Data were analyzed from April 30, 2021, through June 29, 2023.InterventionsVLED alone for 6 weeks or VLED for 6 weeks after RYGB; both interventions were preceded by 3-week LED.Main Outcomes and MeasuresBetween-group comparisons of 6-week changes in CV risk factors.ResultsAmong 78 patients included in the analyses, the mean (SD) age was 47.5 (9.7) years; 51 (65%) were women, and 27 (35%) were men. Except for a slightly higher mean (SD) body mass index of 44.5 (6.2) in the RYGB group (n = 41) vs 41.9 (5.4) in the VLED group (n = 37), baseline demographic and clinical characteristics were similar between groups. Major atherogenic blood lipids (low-density lipoprotein cholesterol, non–high-density lipoprotein cholesterol, apolipoprotein B, lipoprotein[a]) were reduced after RYGB in comparison with VLED despite a similar fat mass loss. Mean between-group differences were −17.7 mg/dL (95% CI, −27.9 to −7.5), −17.4 mg/dL (95% CI, −29.8 to −5.0) mg/dL, −9.94 mg/dL (95% CI, −15.75 to −4.14), and geometric mean ratio was 0.55 U/L (95% CI, 0.42 to 0.72), respectively. Changes in glycemic control and blood pressure were similar between groups.Conclusions and RelevanceThis study found that clinically meaningful reductions in major atherogenic blood lipids were demonstrated after RYGB, indicating that RYGB may reduce CV risk independent of weight loss.Trial RegistrationClinicalTrials.gov Identifier: NCT02386917

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Impact of body weight, low energy diet and gastric bypass on drug bioavailability, cardiovascular risk factors and metabolic biomarkers: protocol for an open, non-randomised, three-armed single centre study (COCKTAIL)

Cited by 21 publications

References 69 publications

Drug Disposition Protein Quantification in Matched Human Jejunum and Liver From Donors With Obesity

Drug Disposition Protein Quantification in Matched Human Jejunum and Liver From Donors With Obesity

Neither Gastric Bypass Surgery Nor Diet-Induced Weight-Loss Affect OATP1B1 Activity as Measured by Rosuvastatin Oral Clearance

Gastric Bypass vs Diet and Cardiovascular Risk Factors

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