Relevance of CYP3A4*20, UGT1A1*37 and UGT1A1*28 variants in irinotecan‐induced severe toxicity. (16th April 2018)

• Record Type: Journal Article
• Authors: Riera, Pau; Salazar, Juliana; Virgili, Anna C.; Tobeña, María; Sebio, Ana; Gallano, Pía; Barnadas, Agustí; Páez, David
• Is Part Of: British journal of clinical pharmacology. Volume 84:Number 6(2018:Dec.)
• Page Start: 1389
• Page End: 1392
• Publication Date: 2018-04-16
• Subjects: colorectal cancer -- CYP3A4*20 -- irinotecan -- toxicity -- UGT1A1*28 -- UGT1A1*37; Pharmacology -- Periodicals; Drugs -- Periodicals; 615.1
• DOI: 10.1111/bcp.13574
• Languages: English
• ISSNs: 0306-5251

Abstract

Abstract : Severe irinotecan‐induced toxicity is associated with UGT1A1 polymorphisms. However, some patients develop side‐effects despite harbouring a normal UGT1A1 genotype. As CYP3A4 is also an irinotecan‐metabolizing enzyme, our study aimed to elucidate the influence of the CYP3A4*20 loss‐of‐function allele in the toxicity profile of these patients. Three‐hundred and eight metastatic colorectal cancer patients treated with an irinotecan‐containing chemotherapy were studied. The presence of CYP3A4*20, UGT1A1*37 and UGT1A1*28 alleles was tested. Associations between these genetic variants and toxicity were evaluated. UGT1A1*28 was significantly associated with severe diarrhoea, neutropenia and asthenia ( P = 0.002, P = 0.037 and P = 0.041, respectively). One patient with the UGT1A1*28/*37 genotype presented with grade IV neutropenia and lethal septic shock. One heterozygous UGT1A1 (*1/*28) patient also carried the CYP3A4*20 allele but did not develop toxicity. We confirm that UGT1A1*37 and UGT1A1*28 are associated with severe toxicity and suggest that the CYP3A4*20 allele does not play a role in irinotecan‐induced toxicity.