Irinotecan-induced diarrhea: functional significance of the polymorphic ABCC2 transporter protein.

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.

• Authors: F A de Jong, T J Scott-Horton, D L Kroetz, H L McLeod, L E Friberg, R H Mathijssen, J Verweij, S Marsh, A Sparreboom
• Journal: Clinical pharmacology and therapeutics (Clin Pharmacol Ther) Vol. 81 Issue 1 Pg. 42-9 (Jan 2007) ISSN: 0009-9236 [Print] United States
• PMID: 17185998 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• ABCC2 protein, human
• Antineoplastic Agents, Phytogenic
• Membrane Transport Proteins
• Multidrug Resistance-Associated Protein 2
• Multidrug Resistance-Associated Proteins
• Irinotecan
• UGT1A1 enzyme
• Glucuronosyltransferase
• Camptothecin

Topics

• Adult
• Aged
• Alleles
• Antineoplastic Agents, Phytogenic (adverse effects, pharmacokinetics, pharmacology)
• Camptothecin (adverse effects, analogs & derivatives, pharmacokinetics, pharmacology)
• Diarrhea (chemically induced)
• Female
• Glucuronosyltransferase (genetics)
• Humans
• Irinotecan
• Male
• Membrane Transport Proteins (genetics)
• Middle Aged
• Multidrug Resistance-Associated Protein 2
• Multidrug Resistance-Associated Proteins (genetics)
• Polymorphism, Single Nucleotide