Irinotecan‐induced Diarrhea: Functional Significance of the Polymorphic ABCC2 Transporter Protein View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2007-01

AUTHORS

FA Jong, TJ Scott‐Horton, DL Kroetz, HL McLeod, LE Friberg, RH Mathijssen, J Verweij, S Marsh, A Sparreboom

ABSTRACT

Interindividual pharmacokinetic variability of the anticancer agent irinotecan is high. Life-threatening diarrhea is observed in up to 25% of patients receiving irinotecan and has been related with irinotecan pharmacokinetics and UGT1A1 genotype status. Here, we explore the association of ABCC2 (MRP2) polymorphisms and haplotypes with irinotecan disposition and diarrhea. A cohort of 167 Caucasian cancer patients who were previously assessed for irinotecan pharmacokinetics (90-min infusion given every 21 days), toxicity, and UGT1A1*28 genotype were genotyped for polymorphisms in ABCC2 using Pyrosequencing. Fifteen ABCC2 haplotypes were identified in the studied patients. The haplotype ABCC2*2 was associated with lower irinotecan clearance (28.3 versus 31.6 l/h; P=0.020). In patients who did not carry a UGT1A1*28 allele, a significant reduction of severe diarrhea was noted in patients with the ABCC2*2 haplotype (10 versus 44%; odds ratio, 0.15; 95% confidence interval, 0.04-0.61; P=0.005). This effect was not observed in patients with at least one UGT1A1*28 allele (32 versus 20%; odds ratio, 1.87; 95% confidence interval, 0.49-7.05; P=0.354). This study suggests that the presence of the ABCC2*2 haplotype is associated with less irinotecan-related diarrhea, maybe as a consequence of reduced hepatobiliary secretion of irinotecan. As the association was seen in patients not genetically predisposed at risk for diarrhea due to UGT1A1*28, confirmatory studies of the relationships of ABCC2 genotypes and irinotecan disposition and toxicity are warranted. More... »

PAGES

42-49

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/sj.clpt.6100019

    DOI

    http://dx.doi.org/10.1038/sj.clpt.6100019

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1035145870

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/17185998


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