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

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• 作者：Sin-Chi Chew (1) (2)
  Joanne Lim (1) (2)
  Onkar Singh (2)
  Xiangai Chen (2)
  Eng-Huat Tan (3)
  Edmund-JD Lee (1)
  Balram Chowbay (2) (4) (5)
  
• 关键词：Asians ; Chinese ; Nasopharyngeal cancer ; Pharmacogenetics ; Regulatory nuclear receptor ; Docetaxel
• 刊名：European Journal of Clinical Pharmacology
• 出版年：2014
• 出版时间：February 2014
• 年：2014
• 卷：70
• 期：2
• 页码：155-166
• 全文大小：432 KB
• 作者单位：Sin-Chi Chew (1) (2)
  Joanne Lim (1) (2)
  Onkar Singh (2)
  Xiangai Chen (2)
  Eng-Huat Tan (3)
  Edmund-JD Lee (1)
  Balram Chowbay (2) (4) (5)
  
  1. Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Drive, Singapore, Singapore, 117597
  2. Laboratory of Clinical Pharmacology, Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre, 11 Hospital Drive, Singapore, Singapore, 169610
  3. Department of Medical Oncology, National Cancer Centre, 11 Hospital Drive, Singapore, Singapore, 169610
  4. Office of Clinical Sciences, Duke–NUS Graduate Medical School Singapore, 8 College Road, Singapore, Singapore, 169857
  5. SingHealth Clinical Phamacology Core, The Academia, SingHealth, 20 College Road, The Academia, Discovery Tower, Singapore, Singapore, 169856
  
• ISSN：1432-1041

文摘

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--0). 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 Cmax, AUC0-?/sub> 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 Cmax and AUC0-?/sub> 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.