评价卡培他滨在乳腺癌和结直肠癌患者中羧酸酯酶(CES1) SNP与药代动力学和不良反应的关系

Merve Yuksel, D. Ozturk, E. Oztas, G. Özhan, Aylin Turker, T. Korkmaz, A. Okyar, Z. Kara
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引用次数: 0

摘要

卡培他滨是一种口服前药,通过包括羧酸酯酶(CES)在内的三步酶促途径转化为5-氟尿嘧啶。药物代谢酶活性的个体间差异可能影响药效和毒性。本研究的目的是评估CES1中单核苷酸多态性(SNP)与卡培他滨药代动力学和不良反应的关系。7例以卡培他滨为基础的化疗(1000-1250 mg/m2)的乳腺癌和结直肠癌患者在第一个周期的第一天给药后0.5、1、2、3和4小时获得血浆样本。采用高压液相色谱-紫外检测器测定卡培他滨的血药浓度。采用逆转录-聚合酶链反应对SNP (rs8192950)进行基因分型。患者的基因型分布为杂合子(57%)、野生(29%)和突变(14%)(p=0.909)。平均血浆曲线下面积(AUC0-4h)为4.60±2.25µg.h/mL,最大血浆浓度(Cmax)为3.19±2.5µg/mL。基因型和AUC值之间差异无统计学意义(p=0.2236),最常见的不良反应为腹泻(p=0.1028)、虚弱(p=0.6456)、贫血(p=0.6456)、呕吐(p=0.3499)。这是第一个评估CES1 (rs8192950)遗传变异与卡培他滨药代动力学和不良反应之间关系的研究。因此,需要在更大的患者群体中进行额外的研究来支持我们的研究。本文引自:Kurtan Yuksel M, Ozturk D, Oztas E, Ozhan G, Altanlar Turker A, Korkmaz T, Okyar A, Pala Kara Z(2019)。评价卡培他滨在乳腺癌和结直肠癌患者中羧酸酯酶(CES1) SNP与药代动力学和不良反应的关系中华医学杂志,49(2):64-69。
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Evaluation of the association of SNP in carboxylesterase enzyme (CES1) with pharmacokinetic and adverse effects of capecitabine in breast and colorectal cancer patients
DOI : 10.26650/IstanbulJPharm.2019.19018 Capecitabine is an oral prodrug and converted to 5-fluorouracil using three-step enzymatic pathways which include carboxylesterase (CES).  Interindividual differences in the activities of drug-metabolizing enzymes may affect efficacy and toxicity. The aim of this study is to evaluate the association of Single nucleotide polymorphisms (SNP) in CES1 with the pharmacokinetic and adverse effects of capecitabine. Plasma samples were obtained from 7 breast and colorectal cancer patients who were treated with capecitabine-based chemotherapy (1000-1250 mg/m2) at 0.5, 1, 2, 3 and 4 hours following drug administration on their first day of the first cycle. The plasma concentrations of the capecitabine were determined by using a high-pressure liquid chromatography-UV detector. SNP (rs8192950) was genotyped using the reverse transcription-polymerase chain reaction. Patients were found to have heterozygote (57%), wild (29%), and mutant (14%) distributions of genotypes (p=0.909). The mean plasma area under the curve (AUC0-4h) was 4.60±2.25 µg.h/mL, and maximum plasma concentration (Cmax) was 3.19±2.5 µg/mL. There were no statistically significant differences between genotypes and AUC values (p=0.2236) and the most frequently observed side effects were diarrhea (p=0.1028), asthenia (p=0.6456), anemia (p=0.6456), emesis (p=0.3499). This is the first study evaluating an association of genetic variation in CES1 (rs8192950) with pharmacokinetic and adverse effects of capecitabine. Therefore, additional study in larger groups of patients is required to support our study.  Cite this article as : Kurtan Yuksel M, Ozturk D, Oztas E, Ozhan G, Altanlar Turker A, Korkmaz T, Okyar A, Pala Kara Z (2019). Evaluation of the association of SNP in carboxylesterase enzyme (CES1) with pharmacokinetic and adverse effects of capecitabine in breast and colorectal cancer patients. Istanbul J Pharm 49 (2): 64-69.
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