Abstract
Purpose
Effects of genetic polymorphisms/variations of ABCB1, ABCC2, ABCG2 and SLCO1B1 in addition to “UGT1A1*28 or *6” on irinotecan pharmacokinetics/pharmacodynamics in Japanese cancer patients were investigated.
Methods
Associations between transporter haplotypes/variations along with UGT1A1*28 or *6 and SN-38 area under the time–concentration curve (AUC) or neutropenia were examined in irinotecan monotherapy (55 patients) and irinotecan–cisplatin-combination therapy (62 patients).
Results
Higher SN-38 AUC values were observed in ABCB1 2677G>T (A893S) (*2 group) for both regimens. Associations of grade 3/4 neutropenia were observed with ABCC2 −1774delG (*1A), ABCG2 421C>A (Q141K) and IVS12 + 49G>T (# IIB) and SLCO1B1 521T>C (V174A) (*15 · 17) in the irinotecan monotherapy, while they were evident only in homozygotes of ABCB1*2, ABCG2 # IIB, SLCO1B1*15 · 17 in the cisplatin-combination therapy. With combinations of haplotypes/variations of two or more genes, neutropenia incidence increased, but their prediction power for grade 3/4 neutropenia is still unsatisfactory.
Conclusions
Certain transporter genotypes additively increased irinotecan-induced neutropenia, but their clinical importance should be further elucidated.
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Acknowledgments
This study was supported in part by the Program for the Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation, and by the Program for the Promotion of Studies in Health Sciences of the Ministry of Health, Labor and Welfare of Japan. We thank Yakult Honsha Co., Ltd (Tokyo, Japan) for providing analytical standards of irinotecan and its metabolites. We also thank Ms. Chie Sudo for her administrative assistance.
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Sai, K., Saito, Y., Maekawa, K. et al. Additive effects of drug transporter genetic polymorphisms on irinotecan pharmacokinetics/pharmacodynamics in Japanese cancer patients. Cancer Chemother Pharmacol 66, 95–105 (2010). https://doi.org/10.1007/s00280-009-1138-y
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DOI: https://doi.org/10.1007/s00280-009-1138-y