Olavo Vicente Neto1, Suziane Raymundo2, Maria Alice Franzoi3, Andiara do Carmo Artmann4, Mariane Tegner4, Victoria Vendramini Müller2, Roberta Zilles Hahn2, Gustavo Vasconcelos Alves3, Gilberto Schwartsmann3, Rafael Linden2, Marina Venzon Antunes5. 1. Graduate Program on Toxicology and Analytical Toxicology, Universidade Feevale, Novo Hamburgo, RS, Brazil. 2. Graduate Program on Toxicology and Analytical Toxicology, Universidade Feevale, Novo Hamburgo, RS, Brazil; Laboratory of Analytical Toxicology, Institute of Health Sciences, Universidade Feevale, Novo Hamburgo, RS, Brazil. 3. Oncology Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil. 4. Laboratory of Analytical Toxicology, Institute of Health Sciences, Universidade Feevale, Novo Hamburgo, RS, Brazil. 5. Graduate Program on Toxicology and Analytical Toxicology, Universidade Feevale, Novo Hamburgo, RS, Brazil; Laboratory of Analytical Toxicology, Institute of Health Sciences, Universidade Feevale, Novo Hamburgo, RS, Brazil. Electronic address: marinaantunes@feevale.br.
Abstract
OBJECTIVE: to evaluate plasma and salivary uracil (U) to dihydrouracil (UH2) ratios as tools for predicting 5-fluorouracil systemic exposure and drug-related severe toxicity, and clinically validate the use of dried saliva spots (DSS) as an alternative sampling strategy for dihydropyrimidine dehydrogenase (DPD) deficiency assessment. METHODS: Pre-chemotherapy plasma, fresh saliva and DSS samples were obtained from gastrointestinal patients (N = 40) for measurement of endogenous U and UH2 concentrations by LC-MS/MS. A second plasma sample collected during 5FU infusion was used for 5FU area under the curve (AUC) determination by HPLC-DAD. Data on toxicity was reported according to CTCAE. RESULTS: 15% of the patients developed severe 5FU-related toxicity, with neutropenia accounting for 67% of the cases. U, UH2 and [UH2,]/[U] were highly correlated between fresh and dried saliva samples (rs = 0.960; rs = 0.828; rs = 0.910, respectively). 5FU AUC ranged from 11.3 to 37.31 mg h L-1, with 46.2% of under-dosed and 10.3% over-dosed patients. The [UH2]/[U] ratios in plasma, fresh saliva and dried saliva samples were moderately correlated with 5FU AUC and adverse events grade, indicating a partial contribution of the variables to drug exposure (r = -0.412, rs = -0.373, rs = 0.377) and toxicity (r = -0.363, rs = -0.523, rs = 0.542). Metabolic ratios were lower in patients with severe toxicity (P < .01 salivary ratios, and P < .5 plasma ratios), and 5FU AUC were in average 47% higher in this group than in moderate toxicity. The diagnostic performance of [UH2]/[U] ratios in fresh saliva and DSS for the identification of patients with severe toxicity were comparable. CONCLUSIONS: The [UH2]/[U] metabolic ratios in plasma, fresh saliva and DSS were significantly associated with 5FU systemic exposure and toxicity degree. This study also demonstrated the applicability of DSS as alternative sampling for evaluating DPD activity.
OBJECTIVE: to evaluate plasma and salivary uracil (U) to dihydrouracil (UH2) ratios as tools for predicting 5-fluorouracil systemic exposure and drug-related severe toxicity, and clinically validate the use of dried saliva spots (DSS) as an alternative sampling strategy for dihydropyrimidine dehydrogenase (DPD) deficiency assessment. METHODS: Pre-chemotherapy plasma, fresh saliva and DSS samples were obtained from gastrointestinalpatients (N = 40) for measurement of endogenous U and UH2 concentrations by LC-MS/MS. A second plasma sample collected during 5FU infusion was used for 5FU area under the curve (AUC) determination by HPLC-DAD. Data on toxicity was reported according to CTCAE. RESULTS: 15% of the patients developed severe 5FU-related toxicity, with neutropenia accounting for 67% of the cases. U, UH2 and [UH2,]/[U] were highly correlated between fresh and dried saliva samples (rs = 0.960; rs = 0.828; rs = 0.910, respectively). 5FU AUC ranged from 11.3 to 37.31 mg h L-1, with 46.2% of under-dosed and 10.3% over-dosed patients. The [UH2]/[U] ratios in plasma, fresh saliva and dried saliva samples were moderately correlated with 5FU AUC and adverse events grade, indicating a partial contribution of the variables to drug exposure (r = -0.412, rs = -0.373, rs = 0.377) and toxicity (r = -0.363, rs = -0.523, rs = 0.542). Metabolic ratios were lower in patients with severe toxicity (P < .01 salivary ratios, and P < .5 plasma ratios), and 5FU AUC were in average 47% higher in this group than in moderate toxicity. The diagnostic performance of [UH2]/[U] ratios in fresh saliva and DSS for the identification of patients with severe toxicity were comparable. CONCLUSIONS: The [UH2]/[U] metabolic ratios in plasma, fresh saliva and DSS were significantly associated with 5FU systemic exposure and toxicity degree. This study also demonstrated the applicability of DSS as alternative sampling for evaluating DPD activity.
Authors: Abhishek Nag; Yuko Kurushima; Ruth C E Bowyer; Philippa M Wells; Stefan Weiss; Maik Pietzner; Thomas Kocher; Johannes Raffler; Uwe Völker; Massimo Mangino; Timothy D Spector; Michael V Milburn; Gabi Kastenmüller; Robert P Mohney; Karsten Suhre; Cristina Menni; Claire J Steves Journal: Hum Mol Genet Date: 2020-03-27 Impact factor: 6.150