Clinical Pharmacology Program, Pharmacology and Experimental Therapeutics Section, Molecular Pharmacology Section, Biostatistics and Data Management Branch, Medical Oncology Branch, and HIV/AIDS Malignancy Branch, National Cancer Institute, Bethesda, MD 20892, USA.
Clin Cancer Res. 2012 Apr 1;18(7):2099-107. doi: 10.1158/1078-0432.CCR-11-2484. Epub 2012 Feb 3.
Several case reports suggest sorafenib exposure and sorafenib-induced hyperbilirubinemia may be related to a (TA)(5/6/7) repeat polymorphism in UGT1A128 (UGT, uridine glucuronosyl transferase). We hypothesized that sorafenib inhibits UGT1A1 and individuals carrying UGT1A128 and/or UGT1A9 variants experience greater sorafenib exposure and greater increase in sorafenib-induced plasma bilirubin concentration.
Inhibition of UGT1A1-mediated bilirubin glucuronidation by sorafenib was assessed in vitro. UGT1A128 and UGT1A93 genotypes were ascertained with fragment analysis or direct sequencing in 120 cancer patients receiving sorafenib on five different clinical trials. Total bilirubin measurements were collected in prostate cancer patients before receiving sorafenib (n = 41) and 19 to 30 days following treatment and were compared with UGT1A1*28 genotype.
Sorafenib exhibited mixed-mode inhibition of UGT1A1-mediated bilirubin glucuronidation (IC(50) = 18 μmol/L; K(i) = 11.7 μmol/L) in vitro. Five patients carrying UGT1A128/28 (n = 4) or UGT1A93/3 (n = 1) genotypes had first dose, dose-normalized areas under the sorafenib plasma concentration versus time curve (AUC) that were in the 93rd percentile, whereas three patients carrying UGT1A128/28 had AUCs in the bottom quartile of all genotyped patients. The Drug Metabolizing Enzymes and Transporters genotyping platform was applied to DNA obtained from six patients, which revealed the ABCC2-24C>T genotype cosegregated with sorafenib AUC phenotype. Sorafenib exposure was related to plasma bilirubin increases in patients carrying 1 or 2 copies of UGT1A128 alleles (n = 12 and n = 5; R(2) = 0.38 and R(2) = 0.77; P = 0.032 and P = 0.051, respectively). UGT1A128 carriers showed two distinct phenotypes that could be explained by ABCC2-24C>T genotype and are more likely to experience plasma bilirubin increases following sorafenib if they had high sorafenib exposure.
This pilot study indicates that genotype status of UGT1A1, UGT1A9, and ABCC2 and serum bilirubin concentration increases reflect abnormally high AUC in patients treated with sorafenib.
有几项病例报告表明，索拉非尼的暴露量和索拉非尼引起的高胆红素血症可能与 UGT1A128（UGT，尿苷二磷酸葡萄糖醛酸转移酶）中的（TA）（5/6/7）重复多态性有关。我们假设索拉非尼抑制 UGT1A1，并且携带 UGT1A128 和/或 UGT1A9 变异体的个体经历更大的索拉非尼暴露量和更大的索拉非尼诱导的血浆胆红素浓度增加。
在体外评估索拉非尼对 UGT1A1 介导的胆红素葡萄糖醛酸化的抑制作用。在五项不同临床试验中接受索拉非尼治疗的 120 名癌症患者中，通过片段分析或直接测序确定 UGT1A128 和 UGT1A93 基因型。在接受索拉非尼治疗之前（n = 41）和治疗后 19 至 30 天，收集前列腺癌患者的总胆红素测量值，并与 UGT1A1*28 基因型进行比较。
索拉非尼在体外对 UGT1A1 介导的胆红素葡萄糖醛酸化显示出混合模式抑制作用（IC（50）= 18 μmol/L；K（i）= 11.7 μmol/L）。5 名携带 UGT1A128/28（n = 4）或 UGT1A93/3（n = 1）基因型的患者的首剂量，剂量标准化的索拉非尼血浆浓度-时间曲线下面积（AUC）在第 93 个百分位数，而 3 名携带 UGT1A128/28 的患者的 AUC 在所有基因分型患者的第 4 个四分位数中。应用药物代谢酶和转运体基因分型平台对 6 名患者的 DNA 进行了分析，结果显示 ABCC2-24C>T 基因型与索拉非尼 AUC 表型共分离。携带 1 或 2 个 UGT1A128 等位基因的患者（n = 12 和 n = 5）的索拉非尼暴露量与血浆胆红素升高有关（R（2）= 0.38 和 R（2）= 0.77；P = 0.032 和 P = 0.051，分别）。UGT1A128 携带者表现出两种不同的表型，这可以通过 ABCC2-24C>T 基因型来解释，如果他们有较高的索拉非尼暴露量，他们更有可能在接受索拉非尼治疗后出现血浆胆红素升高。
这项初步研究表明，UGT1A1、UGT1A9 和 ABCC2 的基因型状态和血清胆红素浓度升高反映了接受索拉非尼治疗的患者异常高的 AUC。
