Role of CYP24A1, VDR and GC gene polymorphisms on deferasirox pharmacokinetics and clinical outcomes.
Sarah AllegraJ CusatoS De FranciaA ArduinoF LongoE PirroD MassanoA De NicolòA PigaA D'AvolioPublished in: The pharmacogenomics journal (2017)
β-Thalassemia patients develop deficiency in vitamin D absorption and liver hydroxylation, resulting in extremely low calcitriol levels. We explored the role of single-nucleotide polymorphisms (SNPs) involved in vitamin D metabolism, transport and activity on deferasirox pharmacokinetics and outcomes (effectiveness trough levels (Ctrough) and the area under the curve (AUC) cutoffs of 20 μg ml-1 and 360 μg ml-1 h-1, respectively; nonresponse AUC limit of 250 μg ml-1 h-1). Ninety-nine β-thalassemic patients were enrolled. Drug plasma Ctrough and AUC were measured by the high-performance liquid chromatography system coupled with an ultraviolet determination method. Allelic discrimination for VDR, CYP24A1, CYP27B1 and GC gene SNPs was performed by real-time PCR. CYP24A1 22776 TT significantly influenced Cmin and negatively predicted it in regression analysis. CYP24A1 3999 CC was associated with Ctrough and Cmin and was a negative predictor of Tmax, whereas CYP24A1 8620 GG seemed to have a role in Ctrough, AUC, t1/2 and Cmin, and was an AUC negative predictor factor. Considering treatment outcome, Cdx2 and GC 1296 were retained in regression analysis as AUC efficacy cutoff negative predictors.
Keyphrases
- end stage renal disease
- chronic kidney disease
- high performance liquid chromatography
- ejection fraction
- newly diagnosed
- genome wide
- peritoneal dialysis
- randomized controlled trial
- systematic review
- prognostic factors
- mass spectrometry
- type diabetes
- metabolic syndrome
- gene expression
- dna methylation
- simultaneous determination
- smoking cessation
- insulin resistance