Pharmacogenetics of Taxanes: Impact of Gene Polymorphisms of Drug Transporters on Pharmacokinetics and Toxicity

Abstract

Interindividual variability in drug response and the emergence of adverse drug effects are the main causes of treatment failure in cancer therapy. Functional membrane drug transporters play important roles in altering pharmacokinetic profile, resistance to treatment, toxicity and patient survival. Pharmacogenetic studies of these transporters are expected to provide new approaches for optimizing therapy. Taxanes are approved for the treatment of various cancers. Circulating taxanes are taken up by SLCO1B3 into hepatocytes. The CYP450 enzymes CYP3A4, CYP3A5 and CYP2C8 are responsible for the conversion of taxanes into their metabolites. Ultimately, ABCB1 and ABCC2 will dispose the metabolites into bile canaliculi. Polymorphisms of genes encoding for proteins involved in the transport and clearance of taxanes reduce excretion of the drugs, leading to development of toxicity in patients. This review addresses current knowledge on genetic variations of transporters affecting taxanes pharmacokinetics and toxicity, and provides insights into future direction for personalized medicine.

KEYWORDS::

• ABC
• ATP-binding cassette
• breast cancer
• docetaxel
• drug transporters
• paclitaxel
• pharmacogenetics
• SLCO1B3
• SNPs
• solute carrier organic anion
• taxanes
• toxicity

Acknowledgements

The authors would like to thank the Ministry of Higher Education (MOHE), Malaysia, for funding.

Financial & competing interests disclosure

The authors received funding from the Ministry of Higher Education (MOHE), Malaysia, for the project entitled ‘Pharmacogenetics of Docetaxel in Malaysian Metastatic Breast Cancer Patients‘ through the Fundamental Research Grant Scheme (04-04-10-848FR). 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.

Additional information

Funding

The authors received funding from the Ministry of Higher Education (MOHE), Malaysia, for the project entitled ‘Pharmacogenetics of Docetaxel in Malaysian Metastatic Breast Cancer Patients‘ through the Fundamental Research Grant Scheme (04-04-10-848FR). 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.