Evaluation of UGT1A1 and CYP3A Genotyping and Single-Point Irinotecan and Metabolite Concentrations as Predictors of the Occurrence of Adverse Events in Cancer Treatment

Purpose The variability on irinotecan (IRI) pharmacokinetics and toxicity has been attributed mostly to genetic variations in the UGT1A1 gene, responsible for conjugation of the active metabolite SN-38. Also, CYP3A mediates the formation of inactive oxidative metabolites of IRI. The association betw...

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Published in:Journal of gastrointestinal cancer 2023-06, Vol.54 (2), p.589-599
Main Authors: Basso, Jeziel, Schwartsmann, Gilberto, Ibaldi, Mariana Rodrigues, Schaefer, Vitoria Daniela, Pavei, Carla Casagrande, Hahn, Roberta Zilles, Antunes, Marina Venzon, Linden, Rafael
Format: Article
Language:English
Subjects:
Cancer Research
Gastroenterology
Internal Medicine
Medicine
Medicine & Public Health
Oncology
Original Research
Radiotherapy
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Summary:Purpose The variability on irinotecan (IRI) pharmacokinetics and toxicity has been attributed mostly to genetic variations in the UGT1A1 gene, responsible for conjugation of the active metabolite SN-38. Also, CYP3A mediates the formation of inactive oxidative metabolites of IRI. The association between the occurrence of severe adverse events, pharmacokinetics parameters, and UGT1A1 and CYP3A4 predicted phenotypes was evaluated, as the evaluation of [SN-38]/IRI dose ratio as predictor of severe adverse events. Methods Forty-one patients undergoing IRI therapy were enrolled in the study. Blood samples were collected 15 min after the end of drug the infusion, for IRI, SN-38, SN-38G, bilirubin concentrations measurements, and UGT1A1 and CYP3A genotype estimation. Data on adverse event was reported. Results Fifteen patients (36.5%) developed grade 3/4 adverse events. A total of 9.8% ( n  = 4) of the patients had UGT1A1 reduced activity phenotype, and 48.7% ( n  = 20) had UGT1A1 and 63.4% ( n  = 26) CYP3A intermediary phenotypes. Severe neutropenia and diarrhea were more prevalent in patients with reduced UGT1A1 in comparison with functional metabolism (50% and 75% versus 0% and 13%, respectively). SN-38 levels and its concentrations adjusted by IRI dose were significantly correlated to toxicity (rs = 0.31 ( p  = 0.05) and rs = 0.425 ( p  
ISSN:1941-6628
1941-6636
DOI:10.1007/s12029-022-00840-0