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.

The Functional Influences of Common ABCB1 Genetic Variants on the Inhibition of P-glycoprotein by Antrodia cinnamomea Extracts

“…Recently, A. cinnamomea has been demonstrated to exhibit anticancer and chemopreventive effects [2]. One of the major obstacles in the current chemotherapies of numerous cancers is multidrug resistance (MDR) [3]. MDR can be an intrinsic or acquired cross-resistance to structurally or pharmacologically unrelated agents.…”

Polymorphisms in Slco1B3 and Nr1I2 as Genetic Determinants of Hematotoxicity of Carboplatin and Paclitaxel Combination

“…Polymorphisms in genes encoding carboplatin-or paclitaxel-metabolizing enzymes and transporters, and those in genes encoding DNA repair proteins may be part of such factors. Many pharmacogenetic studies have been previously conducted for these drugs focusing on polymorphisms in ABCB1, CYP3A4, CYP1B1, CYP2C8 genes as well as in NQO1 and DNA repair genes, and conflicting results were obtained [22][23][24][25][26][27][28]. In the present study, no association between patients' sensitivity to hematotoxicity and polymorphisms of these genes was found.…”

Oral co-administration of elacridar and ritonavir enhances plasma levels of oral paclitaxel and docetaxel without affecting relative brain accumulation

“…Polymorphisms of genes encoding for P-gp and CYP3A4 are currently not known to be related to variability in pharmacokinetics of i.v. administered taxanes (Bosch et al , 2006; Jabir et al , 2012), but after oral administration, polymorphisms of these genes can become more important. Interpatient variability in oral bioavailability of docetaxel is decreased when docetaxel is co-administered with inhibitors of CYP3A or P-gp (Stuurman et al , 2013).…”