Pathway-Based Pharmacogenomics of Gemcitabine Pharmacokinetics in Patients with Solid Tumors

Abstract

Aim: The aim of this study was to evaluate the association of gemcitabine pathway SNPs with detailed pharmacokinetic measures obtained from solid tumor patients receiving gemcitabine-based therapy. Materials & methods: SNPs within nine gemcitabine pathway genes, namely CDA, CMPK, DCK, DCTD, NT5C2, NT5C3, SLC28A1, SLC28A3 and SLC29A1 were analyzed for association with gemcitabine pharmacokinetics. Results: Significant association of gemcitabine clearance with SNPs in NT5C2 was identified. Clearance of 2´,2´-difluorodeoxyuridine, a gemcitabine metabolite was significantly predicted by CDA, SLC29A1 and NT5C2 SNPs. This study reports an association of formation clearance of 2´,2´-difluoro-2´-deoxycytidine triphosphate, an active form of gemcitabine with SNPs within uptake transporters SLC28A1, SLC28A3 and SLC29A1. Conclusion: Genetic variation in gemcitabine pathway genes is associated with its pharmacokinetics and hence could influence gemcitabine response. Our study identified pharmacogenetic markers that could be further tested in larger patient cohorts and could open up opportunities to individualize therapy in solid tumor patients.

Original submitted 10 February 2012; Revision submitted 27 April 2012

KEYWORDS::

• cytidine deaminase
• deoxycytidine kinase
• gemcitabine
• pharmacogenomics
• pharmacokinetics

Acknowledgements

The authors are thankful to D Yee, Director, Masonic Cancer Center (MN, USA), for his insight and expertise in the successful completion of this study. The authors wish to acknowledge L Kruse, study coordinator, for her outstanding contribution of enrolling the study subjects and supervising blood sample collection.

Financial & competing interests disclosure

Analysis of gemcitabine, dFdU and dFdCTP concentrations were conducted by the Clinical Pharmacology Core Laboratory, which is supported in part by Cancer Center Support (MN, USA) grant 5P30 CA77598, and by a Clinical Scholars Award to MN Kirstein. JK Lamba is funded through NCI-R01CA132946. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

Analysis of gemcitabine, dFdU and dFdCTP concentrations were conducted by the Clinical Pharmacology Core Laboratory, which is supported in part by Cancer Center Support (MN, United State of America USA) grant 5P30 CA77598, and by a Clinical Scholars Award to MN Kirstein. JK Lamba is funded through National Cancer Institute NCI-R01CA132946. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.