Allegra Sarah, Cusato Jessica, De Francia Silvia, Longo Filomena, Pirro Elisa, Massano Davide, Piga Antonio, D'Avolio Antonio
Department of Medical Sciences, Unit of Infectious Diseases, Amedeo di Savoia Hospital.
Department of Biological and Clinical Sciences.
Pharmacogenet Genomics. 2018 Jan;28(1):17-22. doi: 10.1097/FPC.0000000000000315.
Patients with β-thalassemia major have extremely low vitamin D levels, owing to reduced intestinal absorption, subicteric tint, and/or iron-induced higher pigmentation. We investigated whether some polymorphisms within the VDR, CYP24A1, CYP27B1, and GC genes could play a role in deferasirox pharmacokinetics in a cohort of pediatric patients.
Eighteen children with β-thalassemia were enrolled. Drug plasma concentrations at the end of dosing interval (Ctrough) and after 0, 2, 4, 6, and 24 h of drug administration were measured by a HPLC-UV method. Allelic discrimination for VDR (TaqI, FokI, BsmI, Cdx2, and ApaI), CYP24A1 (22776, 3999 and 8620), CYP27B1 (2838 and -1260), and GC (1296) single nucleotide polymorphisms was performed by real-time PCR.
CYP24A1 8620 AG/GG group negatively predicted Ctrough in regression analysis (P=0.012). ApaI AA genotype resulted as a negative predictor of Ctrough (P=0.025) and area under the concentration curve (P=0.007); FoKI CC genotype remained as area under the concentration curve positive predictor (P=0.008) and TC/CC group as half-life (t1/2) (P=0.003) and volume of distribution (Vd) (P=0.011) negative one; TaqI TC/CC was retained as a negative predictor of drug maximum concentration (Cmax) (P=0.004). Moreover, GC 1296 TG/GG seemed able to predict lower time to reach drug maximum concentration (Tmax) (P=0.033).
Our preliminary experience suggested the potential usefulness of vitamin D pharmacogenetic to better understand deferasirox interindividual variability, also in pediatric patients.
重型β地中海贫血患者由于肠道吸收减少、黄疸及/或铁诱导的色素沉着增加，维生素D水平极低。我们调查了VDR、CYP24A1、CYP27B1和GC基因中的一些多态性是否会在一组儿科患者的地拉罗司药代动力学中发挥作用。
纳入18例β地中海贫血儿童。采用高效液相色谱-紫外法测定给药间隔结束时（谷浓度）及给药后0、2、4、6和24小时的血浆药物浓度。通过实时聚合酶链反应对VDR（TaqI、FokI、BsmI、Cdx2和ApaI）、CYP24A1（22776、3999和8620）、CYP27B1（2838和-1260）和GC（1296）单核苷酸多态性进行等位基因鉴别。
在回归分析中，CYP24A1 8620 AG/GG组对谷浓度有负向预测作用（P=0.012）。ApaI AA基因型是谷浓度（P=0.025）和浓度曲线下面积（P=0.007）的负向预测因子；FokI CC基因型仍是浓度曲线下面积的正向预测因子（P=0.008），TC/CC组是半衰期（t1/2）（P=0.003）和分布容积（Vd）（P=0.011）的负向预测因子；TaqI TC/CC是药物最大浓度（Cmax）的负向预测因子（P=0.004）。此外，GC 1296 TG/GG似乎能够预测达到药物最大浓度的时间（Tmax）更低（P=0.033）。
我们的初步经验表明，维生素D药物遗传学对于更好地理解地拉罗司的个体间变异性具有潜在作用，在儿科患者中也是如此。
