Endogenous plasma and salivary uracil to dihydrouracil ratios and DPYD genotyping as predictors of severe fluoropyrimidine toxicity in patients with gastrointestinal malignancies

Galarza, Andrés Fernando Andrade; Linden, Rafael; Antunes, Marina Venzon; Hahn, Roberta Zilles; Raymundo, Suziane; Silva, Anne Caroline Cezimbra da; Staggemeier, Rodrigo; Spilki, Fernando Rosado; Schwartsmann, Gilberto

doi:10.1016/j.clinbiochem.2016.07.004

Cited by 24 publications

(25 citation statements)

References 30 publications

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“…As far as we know, this is the first study to investigate the effect of oral food intake on U and DHU plasma levels. U levels and DHU/U ratio are promising biomarkers for DPD enzyme activity, 5‐FU clearance and as a predictor of fluoropyrimidine‐related toxicity . Our recent retrospective study in 550 patients showed that a high pre‐treatment U level (>16 ng ml −1 ) was strongly associated with severe fluoropyrimidine‐related toxicity (OR 5.3, P = 0.009) .…”

Section: Discussionmentioning

confidence: 94%

Food‐effect study on uracil and dihydrouracil plasma levels as marker for dihydropyrimidine dehydrogenase activity in human volunteers

Henricks

Jacobs

Meulendijks

et al. 2018

Brit J Clinical Pharma

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AimsThis study aimed to determine the effect of food intake on uracil and dihydrouracil plasma levels. These levels are a promising marker for dihydropyrimidine dehydrogenase activity and for individualizing fluoropyrimidine anticancer therapy.MethodsA randomized, cross‐over study in 16 healthy volunteers was performed, in which subjects were examined in fasted and fed state on two separate days. In fed condition, a high‐fat, high‐caloric breakfast was consumed between 8:00 h and 8:30 h. Whole blood for determination of uracil, dihydrouracil and uridine plasma levels was drawn on both test days at predefined time points between 8:00 h and 13:00 h.ResultsUracil levels were statistically significantly different between fasting and fed state. At 13:00 h, the mean uracil level in fasting state was 12.6 ± 3.7 ng ml−1 and after a test meal 9.4 ± 2.6 ng ml−1 (P < 0.001). Dihydrouracil levels were influenced by food intake as well (mean dihydrouracil level at 13:00 h in fasting state 147.0 ± 36.4 ng ml−1 and in fed state 85.7 ± 22.1 ng ml−1, P < 0.001). Uridine plasma levels showed curves with similar patterns as for uracil.ConclusionsIt was shown that both uracil and dihydrouracil levels were higher in fasting state than in fed state. This is hypothesized to be an direct effect of uridine plasma levels, which were previously shown to be elevated in fasting state and reduced after intake of food. These findings show that, when assessing plasma uracil and dihydrouracil levels for adaptive fluoropyrimidine dosing in clinical practice, sampling should be done between 8:00 h and 9:00 h after overnight fasting to avoid bias caused by circadian rhythm and food effects.

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Section: Discussionmentioning

confidence: 94%

Food‐effect study on uracil and dihydrouracil plasma levels as marker for dihydropyrimidine dehydrogenase activity in human volunteers

Henricks

Jacobs

Meulendijks

et al. 2018

Brit J Clinical Pharma

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“…Several studies have shown that the DHU/U ratio correlates with clearance of 5-FU and with patients’ risk of toxicity (Gamelin et al , 1999; Ciccolini et al , 2004; Jiang et al , 2004; Boisdron-Celle et al , 2007; Zhou et al , 2007; Kristensen et al , 2010; Wettergren et al , 2012; Mueller et al , 2013; Galarza et al , 2016). However, the clinical applicability of the DHU/U ratio has thus far been limited, mainly due to lack of robust evidence on clinical validity.…”

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confidence: 99%

Pretreatment serum uracil concentration as a predictor of severe and fatal fluoropyrimidine-associated toxicity

et al. 2017

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Background:We investigated the predictive value of dihydropyrimidine dehydrogenase (DPD) phenotype, measured as pretreatment serum uracil and dihydrouracil concentrations, for severe as well as fatal fluoropyrimidine-associated toxicity in 550 patients treated previously with fluoropyrimidines during a prospective multicenter study.Methods:Pretreatment serum concentrations of uracil and dihydrouracil were measured using a validated LC-MS/MS method. The primary endpoint of this analysis was global (any) severe fluoropyrimidine-associated toxicity, that is, grade ⩾3 toxicity according to the NCI CTC-AE v3.0, occurring during the first cycle of treatment. The predictive value of uracil and the uracil/dihydrouracil ratio for early severe fluoropyrimidine-associated toxicity were compared. Pharmacogenetic variants in DPYD (c.2846A>T, c.1679T>G, c.1129-5923C>G, and c.1601G>A) and TYMS (TYMS 5′-UTR VNTR and TYMS 3′-UTR 6-bp ins/del) were measured and tested for associations with severe fluoropyrimidine-associated toxicity to compare predictive value with DPD phenotype. The Benjamini-Hochberg false discovery rate method was used to control for type I errors at level q<0.050 (corresponding to P<0.010).Results:Uracil was superior to the dihydrouracil/uracil ratio as a predictor of severe toxicity. High pretreatment uracil concentrations (>16 ng ml−1) were strongly associated with global severe toxicity (OR 5.3, P=0.009), severe gastrointestinal toxicity (OR 33.7, P<0.0001), toxicity-related hospitalisation (OR 16.9, P<0.0001), as well as fatal treatment-related toxicity (OR 44.8, P=0.001). None of the DPYD variants alone, or TYMS variants alone, were associated with severe toxicity.Conclusions:High pretreatment uracil concentration was strongly predictive of severe, including fatal, fluoropyrimidine-associated toxicity, and is a highly promising phenotypic marker to identify patients at risk of severe fluoropyrimidine-associated toxicity.

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“…Figure shows a flowchart of our search results. After filtering PubMed entries and publications from REFARGEN members, 72 articles were selected, 22 of which examined both pharmacogene(s) and drug(s) from a CPIC guideline (Table ). The remaining 50 articles investigated one or more genes comprised in the guidelines.…”

Section: Resultsmentioning

confidence: 99%

“…Cunha‐Junior et al also explored the use of 13C‐uracyl breath tests to predict 5‐FU toxicity and concluded that it has moderate accuracy in discriminating patients susceptible to severe 5‐FU toxicity vs mild or no toxicity . Galarza et al compared DPYD genotyping vs phenotypic methods as predictors of severe fluoropyrimidine toxicity in gastrointestinal tumours and suggested that the ratio of dihydrouracil [UH2] to uracil [U] concentrations in plasma and saliva may be promising functional metrics for predicting fluoropyrimidine toxicity.…”

Section: Resultsmentioning

confidence: 99%

Pharmacogenomics research and clinical implementation in Brazil

Rodrigues‐Soares

Suarez‐Kurtz

2019

Basic Clin Pharma Tox

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We searched PubMed entries and the Lattes database of Brazilian Pharmacogenetics Network investigators, for pharmacogenetic/genomic (PGx) studies in the Brazilian population, focusing on the drugs and genes included in the Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines. Warfarin was the most extensively studied drug in a PGx context: a genomewide association study targeting warfarin stable dose identified significant signals in VKORC1 and CYP2C9, several PGx dosing algorithms were developed based on these and other genes, and the implications of population admixture on extrapolation of dosing recommendations in the CPIC guidelines were examined. A study in renal transplanted patients disclosed association of CYP3A5*6 and CYP3A5*7 with tacrolimus dosing, which led to addition of these variants to CYP3A5*3 in the CPIC tacrolimus guideline. Studies verified predisposition of HIV-positive carriers of UGT1A1*28 to severe atazanavir-induced hyperbilirubinaemia, intolerance to 5-fluorouracyl in gastrointestinal cancer patients with deleterious DPYD variants, failure of HCV-infected carriers of IFNL3 rs12979860 to obtain a sustained viral response to PEG-IFN-α, and hypersensitivity reactions to abacavir in HIV-positive carriers of HLA-B*57:01. No prospective analyses of drug therapy outcomes or cost-effectiveness assessments of PGx-guided therapy were found. In conclusion, the limited adoption of PGx-informed drug prescription in Brazil reflects combination of recognized barriers to PGx implementation worldwide plus factors specific to the Brazilian population. The latter include rarity/absence of genetic variants on which international PGx guidelines are based (eg HLA-B*15.02 for phenytoin and carbamazepine) and the caveat of extrapolating to the admixed Brazilian population, guidelines based on categorical variables, such as continental ancestry (eg warfarin guidelines), "race" or ethnicity.

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Endogenous plasma and salivary uracil to dihydrouracil ratios and DPYD genotyping as predictors of severe fluoropyrimidine toxicity in patients with gastrointestinal malignancies

Cited by 24 publications

References 30 publications

Food‐effect study on uracil and dihydrouracil plasma levels as marker for dihydropyrimidine dehydrogenase activity in human volunteers

Food‐effect study on uracil and dihydrouracil plasma levels as marker for dihydropyrimidine dehydrogenase activity in human volunteers

Pretreatment serum uracil concentration as a predictor of severe and fatal fluoropyrimidine-associated toxicity

Pharmacogenomics research and clinical implementation in Brazil

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