Pharmacogenetic effects of regulatory nuclear receptors (PXR, CAR, RXRα and HNF4α) on docetaxel disposition in Chinese nasopharyngeal cancer patients

• Published in: European journal of clinical pharmacology 2014-02, Vol.70 (2), p.155-166
• Main Authors: Chew, Sin-Chi, Lim, Joanne, Singh, Onkar, Chen, Xiangai, Tan, Eng-Huat, Lee, Edmund-JD, Chowbay, Balram
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antineoplastic agents; Antineoplastic Agents - blood; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; Asian Continental Ancestry Group - genetics; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Carcinoma; Docetaxel; Female; General aspects; Haplotypes; Hemoglobins - analysis; Humans; Kinetics; Leukocyte Count; Male; Medical sciences; Middle Aged; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms - genetics; Nasopharyngeal Neoplasms - metabolism; Otorhinolaryngology. Stomatology; Pharmacogenetics; Pharmacology; Pharmacology. Drug treatments; Pharmacology/Toxicology; Platelet Count; Polymorphism; Polymorphism, Single Nucleotide; Receptors, Cytoplasmic and Nuclear - genetics; Taxoids - blood; Taxoids - pharmacokinetics; Taxoids - pharmacology; Throat cancer; Tumors; Upper respiratory tract, upper alimentary tract, paranasal sinuses, salivary glands: diseases, semeiology
• ISSN: 0031-6970; 1432-1041
• DOI: 10.1007/s00228-013-1596-3

Purpose This exploratory study was aimed at elucidating the pharmacogenetics of regulatory nuclear receptors (PXR, CAR, RXRα and HNF4α) and their implications on docetaxel pharmacokinetics and pharmacodynamics in local Chinese nasopharyngeal cancer patients. Methods A total of 59 single nucleotide polymorphisms (SNPs), including tag-SNPs and functionally relevant SNPs of the genes encoding these regulatory nuclear receptors (PXR/ NR1I2 , CAR/ NR1I3 , RXRα/ NR2B1 and HNF4α/ NR2A1 ), were profiled in the patients enrolled in our study by direct sequencing ( N  = 50). The generalized linear model was employed to estimate the haplotypic effects on the pharmacokinetics and pharmacodynamics of the patients. Results The pharmacokinetic profiles of docetaxel in these patients were characterized by marked interindividual variability, with approximately four- to sixfold variations observed in C max , AUC 0-∞ and CL. Individual SNP association tests revealed that polymorphisms in NR2B1 and NR2A1 were significantly correlated with altered docetaxel pharmacokinetics. Subsequent haplotype association analysis identified the NR2B1 LD block 2 AG haplotype [*+4458G>A(rs3132291) and *+4988A>G(rs4842198)] to be significantly associated with altered pharmacokinetics, in which patients carrying two copies of the AG haplotype had approximately a 20 % decreased C max and AUC 0-∞ and a 21 % increased CL compared to those who carried only one copy or no copies of the haplotype. A number of SNPs in NR1I2 , NR1I3 , NR2B1 and NR2A1 were also associated with a significant decrease in blood counts from baseline. No haplotype was found to exert any effects on the pharmacodynamics parameters. Conclusions The present exploratory study identified several SNPs in the genes encoding regulatory nuclear receptors which may account for the interpatient variability in docetaxel pharmacokinetics and pharmacodynamics. These findings highlight the important role of regulatory nuclear receptors on the disposition of docetaxel.