Pekka Keski-Rahkonen’s research while affiliated with International Agency for Research on Cancer and other places

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Publications (124)


Identifying metabolomic mediators of the physical activity and colorectal cancer relationship
  • Article

January 2025

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25 Reads

Cancer Epidemiology Biomarkers & Prevention

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Background: Current evidence suggests higher physical activity (PA) levels are associated with a reduced risk of colorectal cancer (CRC). However, the mediating role of the circulating metabolome in this relationship remains unclear. Methods: Targeted metabolomics data from 6,055 participants in the EPIC cohort were used to identify metabolites associated with PA and derive a metabolomic signature of PA levels. PA levels were estimated using the validated Cambridge PA index based on baseline questionnaires. Mediation analyses were conducted in a nested case-control study (1,585 cases, 1,585 controls) to examine whether individual metabolites and the metabolomic signature mediated the PA-CRC association. Results: PA was inversely associated with CRC risk (odds ratio [OR] per category change: 0.90, 95% confidence intervals [CI]: 0.83, 0.97; p-value = 0.009). PA levels were associated with 24 circulating metabolites after false discovery rate correction (FDR), with the strongest associations observed for phosphatidylcholine acyl-alkyl (PC ae) C34:3 (FDR-adjusted p-value = 1.18 × 10⁻¹⁰) and lysophosphatidylcholine acyl (lysoPC a) C18:2 (FDR-adjusted p-value = 1.35 × 10⁻⁶). PC ae C34:3 partially mediated the PA-CRC association (natural indirect effect: 0.991, 95% CI: 0.982, 0.999; p-value = 0.04), explaining 7.4% of the association. No mediation effects were observed for the remaining metabolites or the overall PA metabolite signature. Conclusions: PC ae C34:3 mediates part of the PA-CRC inverse association, but further studies with improved PA measures and extended metabolomic panels are needed. Impact: These findings provide insights into PA-related biological mechanisms influencing CRC risk and suggest potential targets for cancer prevention interventions.


Publisher Correction: Genetically predicted gut bacteria, circulating bacteria-associated metabolites and pancreatic ductal adenocarcinoma: a Mendelian randomisation study
  • Article
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December 2024

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Genetically predicted gut bacteria, circulating bacteria-associated metabolites and pancreatic ductal adenocarcinoma: a Mendelian randomisation study

October 2024

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39 Reads

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1 Citation

Pancreatic ductal adenocarcinoma (PDAC) has high mortality and rising incidence rates. Recent data indicate that the gut microbiome and associated metabolites may play a role in the development of PDAC. To complement and inform observational studies, we investigated associations of genetically predicted abundances of individual gut bacteria and genetically predicted circulating concentrations of microbiome-associated metabolites with PDAC using Mendelian randomisation (MR). Gut microbiome-associated metabolites were identified through a comprehensive search of Pubmed, Exposome Explorer and Human Metabolome Database. Single Nucleotide Polymorphisms (SNPs) associated by Genome-Wide Association Studies (GWAS) with circulating levels of 109 of these metabolites were collated from Pubmed and the GWAS catalogue. SNPs for 119 taxonomically defined gut genera were selected from a meta-analysis performed by the MiBioGen consortium. Two-sample MR was conducted using GWAS summary statistics from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4), including a total of 8,769 cases and 7,055 controls. Inverse variance-weighted MR analyses were performed along with sensitivity analyses to assess potential violations of MR assumptions. Nominally significant associations were noted for genetically predicted circulating concentrations of mannitol (odds ratio per standard deviation [ORSD] = 0.97; 95% confidence interval [CI]: 0.95–0.99, p = 0.006), methionine (ORSD= 0.97; 95%CI: 0.94-1.00, p = 0.031), stearic acid (ORSD= 0.93; 95%CI: 0.87–0.99, p = 0.027), carnitine = (ORSD=1.01; 95% CI: 1.00-1.03, p = 0.027), hippuric acid (ORSD= 1.02; 95%CI: 1.00-1.04, p = 0.038) and 3-methylhistidine (ORSD= 1.05; 95%CI: 1.01–1.10, p = 0.02). Two gut microbiome genera were associated with reduced PDAC risk; Clostridium sensu stricto 1 (OR: 0.88; 95%CI: 0.78–0.99, p = 0.027) and Romboutsia (OR: 0.87; 95%CI: 0.80–0.96, p = 0.004). These results, though based only on genetically predicted gut microbiome characteristics and circulating bacteria-related metabolite concentrations, provide evidence for causal associations with pancreatic carcinogenesis.


Association of circulating fatty acids with cardiovascular disease risk: Analysis of individual-level data in three large prospective cohorts and updated meta-analysis

October 2024

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39 Reads

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4 Citations

European Journal of Preventive Cardiology

Background Associations of saturated and unsaturated fatty acids (FAs) with cardiovascular disease (CVD) remain controversial. We therefore aimed to investigate the prospective associations of objectively measured FAs with CVD, including incident coronary heart disease (CHD) and stroke, as well as CVD mortality. Methods Circulating FA concentrations expressed as the percentage of total FAs were assayed in 172,891 participants without prior vascular disease at baseline from the European Prospective Investigation into Cancer and Nutrition-CVD (EPIC-CVD) (7,343 CHD; 6,499 stroke), UK Biobank (1,825; 1,474), and INTERVAL (285; 209) cohort studies. Hazard ratio (HR) per 1-standard deviation (SD) higher FA concentrations was estimated using Cox regression models and pooled by random-effects meta-analysis. Systematic reviews with meta-analysis published by 6 May 2023 on associations between FAs and CVDs were systematically searched and updated meta-analyses using random-effects model were conducted. Evidence from randomized controlled trials (RCTs) was also summarized. Results Higher concentrations of total saturated FAs (SFAs) were associated with higher cardiovascular risks in the combined analysis, with differential findings noted for SFA subtypes in further analysis restricted to EPIC-CVD: positive associations for even-chain SFA [HR for CHD 1.24 (95% CI: 1.18-1.32); stroke 1.23 (1.10-1.38)] and negative associations for odd-chain [0.82 (0.76-0.87); 0.73 (0.67-0.78)] and longer-chain [0.95 (0.80-1.12); 0.84 (0.72-0.99)] SFA. In the combined analysis, total n-3 polyunsaturated FA (PUFA) [0.91 (0.85-0.97)], including docosahexaenoic acid (DHA) [0.91 (0.84-0.98)], was negatively associated with incident CHD risk. Similarly, total n-6 PUFA [0.94 (0.91-0.98)], including linoleic acid (LA) [0.89 (0.83-0.95)], was negatively associated with incident stroke risk. By contrast, more detailed analyses in EPIC-CVD revealed that several downstream n-6 PUFAs of LA were positively associated with CHD risk. Updated meta-analyses of 37 FAs including 49 non-overlapping studies, involving between 7,787 to 22,802 CHD and 6,499 to 14,221 stroke cases, showed broadly similar results as our combined empirical analysis and further suggested significant inverse associations of individual long-chain n-3 PUFAs and LA on both CHD and stroke. The findings of long-chain n-3 PUFAs were consistent with those from published RCTs on CHD despite insufficient evidence in monotherapy, while RCT evidence remained unclear for the rest of the explored FAs. Conclusions Our study provides an overview of the most recent evidence on the associations between objectively measured FAs and CVD outcomes. Collectively, the data reveals notable differences in associations by SFA subtypes and calls for further studies, especially RCTs, to explore these links.


Association of Ultraprocessed Foods Intake with Untargeted Metabolomics Profiles in Adolescents and Young Adults in the DONALD Cohort Study

September 2024

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20 Reads

Journal of Nutrition

Background High consumption of ultraprocessed foods (UPFs) continues to draw significant public health interest because of the associated negative health outcomes. Metabolomics can contribute to the understanding of the biological mechanisms through which UPFs may influence health. Objectives To investigate urine and plasma metabolomic biomarkers of UPF intake in adolescents and young adults. Methods We used data from the Dortmund Nutritional and Anthropometric Longitudinally Designed study to investigate cross-sectional associations of UPF intake with concentrations of urine metabolites in adolescents using 3d weighed dietary records (3d-WDR) and 24-h urine samples (n = 339), and associations of repeatedly assessed UPF intake with concentrations of circulating plasma metabolites in young adults with 3–6 3d-WDRs within 5 y preceding blood measurement (n = 195). Urine and plasma samples were analyzed using mass spectrometry-based metabolomics. Biosample-specific metabolite patterns (MPs) were determined using robust sparse principal components analysis. Multivariable linear regression models were applied to assess the associations of UPF consumption (as a percentage of total food intake in g/d) with concentrations of individual metabolites and MP scores. Results The median proportion of UPF intake was 22.0% [interquartile range (IQR): 12.3, 32.9] in adolescents and 23.2% (IQR: 16.0, 31.6) in young adults. We identified 42 and 6 UPF intake-associated metabolites in urine and plasma samples, respectively. One urinary MP, “xenobiotics and amino acids” [β = 0.042, 95% confidence interval (CI): 0.014, 0.070] and 1 plasma MP, “lipids, xenobiotics, and amino acids” (β = 0.074, 95% CI: 0.031, 0.117) showed positive association with UPF intake. Both patterns shared 29 metabolites, mostly of xenobiotic metabolism. Conclusions We identified urine and plasma metabolites associated with UPF intake in adolescents and young adults, which may represent some of the biological mechanisms through which UPFs may influence metabolism and health.


Simplified schematic representation of the tryptophan–kynurenine pathway. Kynurenine pathway metabolites addressed in this study are highlighted in dark blue.
Study enrollment flow chart for the FOCUS Consortium.
Selected Kaplan–Meier survival curves for unadjusted associations between tryptophan–kynurenine pathway metabolite concentrations with all‐cause mortality by tertiles among stage I–III colorectal cancer patients from the FOCUS Consortium. p value was calculated using log‐rank statistics. Tryptophan, T1: 10.8–55.4 nmol/L; T2: 55.4–67.3 nmol/L; T3: >67.3.1 nmol/L. Kyn, T1: 0.6–1.5 nmol/L; T2: 1.5–1.8 nmol/L; T3: >1.8 nmol/L. AA, T1: 3.4–13.9 nmol/L; T2: 13.9–19.3 nmol/L; T3: >19.3 nmol/L. HK, T1: 1.6–38.2 nmol/L; T2: 38.3–53.4 nmol/L; T3: >53.5 nmol/L. QA, T1: 74.2–390.0 nmol/L; T2: 391.0–544.0 nmol/L; T3: >545.0 nmol/L. Kyn/Trp ratio, T1: 0.012–0.024; T2: 0.024–0.030; T3: >0.030. AA, Anthranilic acid; FOCUS, folate‐dependent 1‐carbon metabolism in colorectal cancer recurrence and survival; HK, 3‐Hydroxykynurenine; Kyn, Kynurenine; QA, Quinolinic acid; T, tertile; Trp, Tryptophan.
Circulating tryptophan–kynurenine pathway metabolites are associated with all‐cause mortality among patients with stage I–III colorectal cancer

September 2024

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46 Reads

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2 Citations

Alterations within the tryptophan–kynurenine metabolic pathway have been linked to the etiology of colorectal cancer (CRC), but the relevance of this pathway for prognostic outcomes in CRC patients needs further elucidation. Therefore, we investigated associations between circulating concentrations of tryptophan–kynurenine pathway metabolites and all‐cause mortality among CRC patients. This study utilizes data from 2102 stage I–III CRC patients participating in six prospective cohorts involved in the international FOCUS Consortium. Preoperative circulating concentrations of tryptophan, kynurenine, kynurenic acid (KA), 3‐hydroxykynurenine (HK), xanthurenic acid (XA), 3‐hydroxyanthranilic acid (HAA), anthranilic acid (AA), picolinic acid (PA), and quinolinic acid (QA) were measured by liquid chromatography–tandem mass spectrometry. Using Cox proportional hazards regression, we examined associations of above‐mentioned metabolites with all‐cause mortality, adjusted for potential confounders. During a median follow‐up of 3.2 years (interquartile range: 2.2–4.9), 290 patients (13.8%) deceased. Higher blood concentrations of tryptophan, XA, and PA were associated with a lower risk of all‐cause mortality (per doubling in concentrations: tryptophan: HR = 0.56; 95%CI:0.41,0.76, XA: HR = 0.74; 95%CI:0.64,0.85, PA: HR = 0.76; 95%CI:0.64,0.92), while higher concentrations of HK and QA were associated with an increased risk of death (per doubling in concentrations: HK: HR = 1.80; 95%CI:1.47,2.21, QA: HR = 1.31; 95%CI:1.05,1.63). A higher kynurenine‐to‐tryptophan ratio, a marker of cell‐mediated immune activation, was associated with an increased risk of death (per doubling: HR = 2.07; 95%CI:1.52,2.83). In conclusion, tryptophan–kynurenine pathway metabolites may be prognostic markers of survival in CRC patients.



FIGURE 1. Flow diagram of the study sample selection in the discovery cohort (IDEFICS/I.Family). Abbreviations: CEHQ, Children's Eating Habits Questionnaire; FFQ, food frequency questionnaire; 24-HDR, 24-h dietary recall.
Number of short-term consumers of the food groups in the IDEFICS/ I.Family cohort by study time points.
Overview of the identified short-term and/or habitual dietary intake-metabolite associations in the IDEFICS/I.Family cohort.
Median habitual dietary intake of the food groups in the IDEFICS/I.Family cohort by study time points. Dietary intake (g/d) W1, n ¼ 597 W2, n ¼ 596 W3, n ¼ 595
Identification and Replication of Urine Metabolites Associated With Short-Term and Habitual Intake of Sweet and Fatty Snacks in European Children and Adolescents

September 2024

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36 Reads

Journal of Nutrition

Background Intake of sweet and fatty snacks may partly contribute to the occurrence of obesity and other health conditions in childhood. Traditional dietary assessment methods may be limited in accurately assessing the intake of sweet and fatty snacks in children. Metabolite biomarkers may aid the objective assessment of children’s food intake and support establishing diet–disease relationships. Objectives The present study aimed to identify biomarkers of sweet and fatty snack intake in 2 independent cohorts of European children. Methods We used data from the IDEFICS/I.Family cohort from baseline (2007/2008) and 2 follow-up examination waves (2009/2010 and 2013/2014). In total, 1788 urine samples from 599 children were analyzed for untargeted metabolomics using high-resolution liquid chromatography-mass spectrometry. Short-term dietary intake was assessed by 24-h dietary recalls, and habitual dietary intake was calculated with the National Cancer Institute method. Data from the Dortmund Nutritional and Anthropometric Longitudinal Designed (DONALD) cohort of 24-h urine samples (n = 567) and 3-d weighted dietary records were used for external replication of results. Multivariate modeling with unbiased variable selection in R algorithms and linear mixed models were used to identify novel biomarkers. Metabolite features significantly associated with dietary intake were then annotated. Results In total, 66 metabolites were discovered and found to be statistically significant for chocolate candy; cakes, puddings, and cookies; candy and sweets; ice cream; and crisps. Most of the features (n = 62) could not be annotated. Short-term and habitual chocolate intake were positively associated with theobromine, xanthosine, and cyclo(L-prolyl-L-valyl). These results were replicated in the DONALD cohort. Short-term candy and sweet intake was negatively associated with octenoylcarnitine. Conclusions Of the potential metabolite biomarkers of sweet and fatty snacks in children, 3 biomarkers of chocolate intake, namely theobromine, xanthosine, and cyclo(L-prolyl-L-valyl), are externally replicated. However, these potential biomarkers require further validation in children.


Metabolomics signatures of sweetened beverages and added sugar are related to anthropometric measures of adiposity in young individuals: results from a cohort study

July 2024

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20 Reads

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2 Citations

American Journal of Clinical Nutrition

Background The associations of sweetened beverages (SBs) and added sugar (AS) intake with adiposity are still debated. Metabolomics could provide insights into the mechanisms linking their intake to adiposity. Objectives We aimed to identify metabolomics biomarkers of intake of low- and no-calorie sweetened beverages (LNCSBs), sugar-sweetened beverages (SSBs), and ASs and to investigate their associations with body mass index, body fat percentage, and waist circumference. Methods We analyzed 3 data sets from the Dortmund Nutritional and Anthropometric Longitudinally Designed (DONALD) cohort study, of children who provided 2 urine samples (n = 297), adolescents who provided a single urine sample (n = 339), and young adults who provided a single plasma sample (n = 195). Urine and plasma were analyzed using untargeted metabolomics. Dietary intakes were assessed using 3-d weighed dietary records. The random forest, partial least squares, and least absolute shrinkage and selection operator were jointly used for metabolite selection. We examined associations of intakes with metabolites and anthropometric measures using linear and mixed-effects regression. Results In adolescents, LNCSB were positively associated with acesulfame (β: 0.0012; 95% confidence interval [CI]: 0.0006, 0.0019) and saccharin (β: 0.0009; 95% CI: 0.0002, 0.0015). In children, the association was observed with saccharin (β: 0.0016; 95% CI: 0.0005, 0.0027). In urine and plasma, SSBs were positively associated with 1-methylxanthine (β: 0.0005; 95% CI: 0.0003, 0.0008; and β: 0.0010, 95% CI 0.0004, 0.0015, respectively) and 5-acetylamino-6-amino-3-methyluracil (β: 0.0005; 95% CI: 0.0002, 0.0008; and β: 0.0009; 95% CI: 0.0003, 0.0014, respectively). AS was associated with urinary sucrose (β: 0.0095; 95% CI: 0.0069, 0.0121) in adolescents. Some of the food-related metabolomics profiles were also associated with adiposity measures. Conclusions We identified SBs- and AS-related metabolites, which may be important for understanding the interplay between these intakes and adiposity in young individuals.


Citations (65)


... Therefore, MR serves as the most appropriate strategy for investigating the causal relationship between the gut microbiome, associated circulating metabolites, and PDAC risk. Daniel et al. [79] conducted a com-prehensive investigation into the associations between genetically predicted abundances of individual gut microbiota and the genetically predicted circulating concentrations of microbiome-associated metabolites, specifically in the context of PDAC, employing the methodology of MR. The results of this study, although predicated exclusively on genetically predicted characteristics of the gut microbiome and their corresponding metabolite concentrations, furnish compelling evidence for causal associations with the etiology of pancreatic carcinogenesis [79]. ...

Reference:

The Use of Personalized Medicine in Pancreatic Ductal Adenocarcinoma (PDAC): New Therapeutic Opportunities
Genetically predicted gut bacteria, circulating bacteria-associated metabolites and pancreatic ductal adenocarcinoma: a Mendelian randomisation study

... Differences found in our work for these two compounds could reflect differential intake of caffeic acid and tryptophan or alterations in the metabolism of these two precursors. In this respect, a dysregulation of tryptophan metabolism has been linked to colorectal tumorigenesis [41], and elevated levels of circulating tryptophan-kynurenine pathway metabolites were associated with worse prognosis in patients with CRC [42]. ...

Circulating tryptophan–kynurenine pathway metabolites are associated with all‐cause mortality among patients with stage I–III colorectal cancer

... Another notable monomethylxanthine is 1-methylxanthine (1-MX), a caffeine derivative and a urinary metabolite of caffeine and theobromine in humans [49]. In the molecular structure of 1-MX, there is a purine ring with a methyl group at the N-1 position. ...

Metabolomics signatures of sweetened beverages and added sugar are related to anthropometric measures of adiposity in young individuals: results from a cohort study
  • Citing Article
  • July 2024

American Journal of Clinical Nutrition

... After the first few years of life, the microbiota becomes more stable and "adult-like" in its composition (4), but it could be still perturbated by dietary choices, hormones, antibiotics and pollution (5)(6)(7)(8). The resistance and resilience of the gut microbiota depends on various reasons: -diversity; -functional redundancy;-adaptive capacity;-intermicrobial interactions;-host immunity;-diet;-environmental consistency, which means the stability of nutrients, pH and oxygen level;-gut habitat complexity, i.e., having different anatomical and functional units such as folds and crypts allowing more stable bacterial reservoirs (9). ...

Multiomic Signatures of Traffic-Related Air Pollution in London Reveal Potential Short-Term Perturbations in Gut Microbiome-Related Pathways
  • Citing Article
  • May 2024

Environmental Science and Technology

... First, we present study-level inclusion prevalence estimates for the 43 detected mutational signatures, as shown in Figure 4. We find that several mutational signatures, including SBS1, SBS2, SBS8, SBS13, SBS18, and SBS39, exhibit high prevalence in multiple cancer types, consistent with previous findings Alexandrov et al. (2020). Additionally, we detect the recently defined SBS40a and SBS40b (Senkin et al., 2024). Notably, mutational signatures associated with tobacco smoking, such as SBS4 and SBS92, are more prevalent in lung squamous cell carcinoma, which is known to be strongly associated with smoking, compared to lung adenocarcinoma and head squamous cell carcinoma, which are associated with smoking but can occur in nonsmokers (Subramanian and Govindan, 2007;Dahlstrom et al., 2008). ...

Geographic variation of mutagenic exposures in kidney cancer genomes

Nature

... Alterations in PC metabolism, especially in levels of certain PC species, have been linked to breast, liver, and colorectal cancers. These alterations reflect the metabolic reprogramming of cancer cells to support rapid cell growth and membrane biogenesis [51][52][53]. Sphingolipids are involved in regulating cell death, proliferation, and differentiation. The dysregulation of sphingolipid metabolism is associated with cancer progression [82,83]. ...

Association between pre-diagnostic circulating lipid metabolites and colorectal cancer risk: a nested case-control study in the European Prospective Investigation into Cancer and Nutrition (EPIC)

EBioMedicine

... Endogenous estrogens play complex and ambiguous roles in the development of DTC, especially among females during perimenopause (27). Furthermore, higher levels of testosterone and androstenedione increase the risk of DTC in pre/perimenopausal women, but not men or postmenopausal women (28), suggesting that regulation of sex hormones in TC is complex and dynamic. ...

Circulating endogenous sex steroids and risk of differentiated thyroid carcinoma in men and women

... Studies have shown mixed results regarding the relationship between coffee consumption and the risk of colon cancer (Oyelere et al., 2024). Case-control studies suggest a lower risk of colon cancer with higher coffee intake, while prospective cohort studies don't show the same association, this could be due to biases in case-control studies regarding recalling coffee consumption and selecting control groups (Li et al., 2013). ...

Coffee consumption is associated with a reduced risk of colorectal cancer recurrence and all‐cause mortality

... Recently, the national, multicenter phase-III registered clinical trial aims to analyze physical activity and cancer-related fatigue in enrolled metastatic TGCT patients treated with cisplatinbased chemotherapy combined with etoposide+/-bleomycin. Moreover, the authors will assess how the gut microbiome affects the connection between physical activities and sequelae (Noh et al., 2024). The long-term goal of the clinical trial NCT05819827 was to investigate associations between chemotherapy-induced nausea and changes in the gut microbiome as well as metabolic pathways in patients with testicular cancer, as well as other genitourinary malignancies such as bladder and prostate cancer. ...

Impact of a one-year supervised physical activity program on long-term cancer-related fatigue and mediating effects of the gut microbiota in metastatic testicular cancer patients: protocol of the prospective multicentre, randomized controlled phase-III STARTER trial

BMC Cancer

... This immunosuppressant has been studied extensively in the past decades, providing a comprehensive overview of CsA metabolites in bile, blood, and urine [17][18][19]. In addition, recent findings suggest the presence of various CsA-related signals of very high abundance in urine samples from CsA users, which seems counterintuitive given that this drug is primarily excreted in feces [20]. A PMx study targeting this drug could, thus, demonstrate its discovery potential by confirming previously identified metabolites and potentially uncovering novel insights into CsA metabolism. ...

High-abundance peaks and peak clusters associate with pharmaceutical polymers and excipients in urinary untargeted clinical metabolomics data: exploration of their origin and possible impact on label-free quantification

The Analyst