| 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
(Affiliation: Department of Medical Oncology, Erasmus University Medical Center, Daniel den Hoed Cancer Center, Rotterdam, The Netherlands.)
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| Journal | Clinical pharmacology and therapeutics
(Clin Pharmacol Ther)
Vol. 81
Issue 1
Pg. 42-9
(Jan 2007)
ISSN: 0009-9236 United States |
| PMID | 17185998
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
|
| Chemical References |
- Antineoplastic Agents, Phytogenic
- Membrane Transport Proteins
- Multidrug Resistance-Associated Proteins
- multidrug resistance-associated protein 2
- irinotecan
- Camptothecin
- bilirubin uridine-diphosphoglucuronosyl transferase 1A1
- Glucuronosyltransferase
|
| 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
- Male
- Membrane Transport Proteins
(genetics)
- Middle Aged
- Multidrug Resistance-Associated Proteins
(genetics)
- Polymorphism, Single Nucleotide
|
