Lack of Association of Single-Nucleotide Polymorphisms in Pregnane X Receptor, Hepatic Nuclear Factor 4α, and Constitutive Androstane Receptor with Docetaxel Pharmacokinetics

Abstract

Purpose:This study aims to describe a population pharmacokinetic model for docetaxel in Asian breast cancer patients and to evaluate the effects of single-nucleotide polymorphisms (SNP) in the cytochrome P450 3A (CYP3A) gene expression regulators, constitutive androstane receptor (CAR), pregnane X receptor (PXR), and hepatic nuclear factor 4a (HNF4a), on the pharmacokinetics of docetaxel. Experimental Design: Docetaxel was given as an i.v. infusion of 75 mg/m 2 over 1 h to 101 female breast cancer patients. CAR, PXR, and HNF4a were comprehensively sequenced. Docetaxel concentrations were measured using a liquid chromatography/tandem mass spectrometry method and its population pharmacokinetic variables, and the covariate effects of clearance predictors were estimated using a nonlinear mixed effects model. Results: Final estimates for docetaxel clearance was 47.1 L/h/70 kg/1.75 m. Between subject variability in docetaxel clearance was 22.5%. Covariates that showed significant association with docetaxel clearance included body size, a1acid glycoprotein and liver function. SNPs identified in the coding regions of CAR and HNF4a and 5 ¶ untranslated region of PXR in this Asian breast cancer cohort did not seem to improve predictability of docetaxel clearance. Conclusions: SNPs identified in CYP3A gene expression regulators CAR, HNF4a, and PXR in the Asian female breast cancer population do not seem to have any significant effect on the clearance of docetaxel, a CYP3A substrate.

Pharmacogenetics in Breast Cancer Therapy

“…Incorporating common polymorphisms of PXR, CAR, and HNF4a and CYP3A5*3C with other covariables in a nonlinear mixed effect model (NONMEM) for docetaxel clearance showed no significant contribution from these polymorphisms in explaining variability of clearance (74).…”

The Making of a CYP3A Biomarker Panel for Guiding Drug Therapy

“…In one study, rs2472677 has been associated with unboosted atazanavir clearance [72], while a PXR haplotype was found to be associated with CYP3A4 and ABCB1 mRNA expression and doxorubicin clearance in Asian breast cancer patients [73]. Yet, further results failed to confirm associations between PXR , CAR and HNF4α genotype and docetaxel/doxorubicin pharmacokinetics [74,75]. These studies suggest that polymorphisms in transcription factors have the potential to affect CYP3A4 expression, but likely account only for a portion of inter-individual variability in CYP3A4 expression and enzyme activity, being confounded by environmental conditions that impact multiple transcription factor expression.…”

Hepatic OATP1B Transporters and Nuclear Receptors PXR and CAR: Interplay, Regulation of Drug Disposition Genes, and Single Nucleotide Polymorphisms

“…Nevertheless the nonsynonymous variants p.Arg98Cys, p.Arg148Gln, p.Glu158Lys, p.Arg381Trp and p.Ile403 Val have been shown to result in reduced PXR activity in vitro and therefore have the potential to contribute to interindividual variability in drug disposition. − Importantly, it should be noted that most of the identified SNPs in the coding region of NR1I2 are rare and, thus, unlikely to be a major factor in PXR-mediated target gene activation in a given population. In contrast, SNPs in the untranslated regions of the gene are more frequent and have been linked to phenotypic changes such as altered target gene expression or doxorubicin clearance, , but published data to date have not been consistent. , It should be noted that genetic variants of PXR (namely, the -25385T>C and -24381A>C and -24113G>A linkage disequilibrium) have been associated with diseases including inflammatory bowel diseases (IBD) such as Crohn’s disease and ulcerative colitis. , However, the overall contribution of PXR polymorphisms to complex multifactorial diseases such as ulcerative colitis or Crohn’s disease needs additional prospective clinical studies.…”