Irinotecan-induced Diarrhea: Functional Significance of the Polymorphic ABCC2 Transporter Protein

doi:doi:10.1038/sj.clpt.6100019

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Clinical Pharmacology & Therapeutics (2007) 81, 42–49. doi:10.1038/sj.clpt.6100019

Irinotecan-induced Diarrhea: Functional Significance of the Polymorphic ABCC2 Transporter Protein

Previously presented at the 2006 Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics, Baltimore, MD, 10 March 2006.

F A de Jong¹, T J Scott-Horton², D L Kroetz³, H L McLeod², L E Friberg⁴, R H Mathijssen¹, J Verweij¹, S Marsh² and A Sparreboom^1,5

¹Department of Medical Oncology, Erasmus University Medical Center – Daniel den Hoed Cancer Center, Rotterdam, The Netherlands
²Department of Medicine, Washington University School of Medicine, St Louis, Missouri, USA
³Department of Biopharmaceutical Sciences, University of California, San Francisco, California, USA
⁴Division of Pharmacokinetics and Drug Therapy, Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden
⁵Clinical Pharmacology Research Core, National Cancer Institute, Bethesda, Maryland, USA

Correspondence: A Sparreboom, (alex.sparreboom@stjude.org)

Received 14 June 2006; Accepted 2 October 2006.

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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.