Role of pharmacogenetics on exemestane metabolism and toxicity

药物遗传学对依西美坦代谢和毒性的作用

• 批准号: 8527745
• 负责人: Philip Lazarus
• 金额: $ 51.33万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-09 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8527745
• 关键词: Accounting; Adjuvant; Adverse event; Affect; Aromatase; Aromatase Inhibitors; Arthralgia; Breast; Breast Cancer Prevention; Breast Cancer Treatment; Cancer Patient; Cell Fraction; Cell Line; Chemoprevention; Chemopreventive Agent; Clinical Data; Clinical Trials; Code; Correlative Study; Data; Development; Double-Blind Method; Enzyme Gene; Enzymes; Estrogen receptor positive; Excretory function; Exemestane; Exhibits; Gene Deletion; Gene Frequency; Generations; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genomics; Genotype; Glucuronides; Glucuronosyltransferase; Goals; Haplotypes; Hot flushes; Human; In Vitro; Individual; Individual Differences; Kinetics; Lead; Liver; Malignant Neoplasms; Measures; Mediating; Medical center; Medicine; Metabolic; Metabolic Pathway; Metabolism; Multicenter Trials; National Cancer Institute of Canada Clinical Trials Group; Outcome; Pathway interactions; Patient Care; Patients; Pharmaceutical Preparations; Pharmacogenetics; Phase; Phenotype; Placebo Control; Placebos; Plasma; Play; Population; Postmenopause; Prevention; Process; Proteins; Randomized; Reaction; Recruitment Activity; Research; Risk; Risk Reduction; Role; Sampling; Serum; Source; Staging; System; Tamoxifen; Therapeutic; Therapeutic Effect; Tissues; Toxic effect; Treatment Efficacy; United States National Institutes of Health; Urine; Variant; Woman; clinical efficacy; drug metabolism; enzyme activity; enzyme pathway; genetic profiling; hormone therapy; in vitro activity; in vivo; interest; malignant breast neoplasm; response; standard of care; urinary

DESCRIPTION (provided by applicant): Aromatase inhibitors (AIs) are widely used as adjuvant treatment for estrogen-receptor positive breast cancer in post-menopausal women. AIs have been demonstrated to have equal to or greater efficacy and less toxicity than tamoxifen (TAM), the drug of choice for many years. Exemestane (EXE) is a 3rd-generation AI that has demonstrated efficacy in the treatment of breast cancer patients, and as with TAM and other AIs, there has been considerable inter-individual variability in overall response to EXE and in the occurrence of toxicities, but the causes of this variability have not been elucidated. Differences in drug metabolism can be a source of variability between patients. Genetic variations occur in several of the enzymes involved in phase I and II metabolic reactions and many of these can lead to alterations in enzyme activity which in turn can alter therapeutic response to drugs. EXE is extensively metabolized as unchanged EXE and is found at less than 1% in urine and 10% in plasma. We have characterized the EXE metabolism pathway and have identified the enzymes most active in this process. One of the key metabolic steps is the reduction of the 17-keto group to form 17-dihydroexemestane (17-OH-EXE), a metabolite that exhibits significant anti-aromatase activity in vitro and which is extensively glucuronidated by UDP-glucuronosyltransferases (UGTs) for excretion in the urine. In preliminary studies, we have shown that a deletion polymorphism in UGT2B17 may have a significant impact on the disposition of EXE in liver and thus potentially on its therapeutic effect. In addition to 17-OH-EXE and its glucuronide, there are 4 other metabolites of EXE, two of which are derived from 17-OH-EXE. Considerable variability in EXE metabolite formation from different individuals was observed in these and previous studies. These data underscore the importance of understanding whether genetic variations may affect an individual's response to the drug. It is our hypothesis that EXE metabolism is an important source of the inter-individual variations in EXE metabolic profiles and those polymorphisms in EXE-metabolizing enzymes play a role in affecting EXE therapeutic efficacy and toxicity. The specific aims of this proposal are to, (1) characterize the EXE metabolism pathway and determine the in vitro effect of functional polymorphisms in enzymes active in EXE metabolism, (2) establish EXE metabolism profile kinetics and determine whether correlations exist in vivo between UGT2B17 deletion genotype and urinary EXE metabolite profiles, and (3) determine whether correlations exist between metabolizing enzyme genotypes, serum EXE metabolite profiles and EXE-induced toxicity and adverse events in a large population of women taking EXE, utilizing samples and clinical data from the NCIC CTG MAP.3 trial that is examining EXE in the chemoprevention and risk reduction setting. Together, these studies will allow us to fully characterize functionally-relevan polymorphisms in the EXE-metabolizing enzyme pathway that are potentially important in EXE clinical efficacy.

描述（由申请方提供）：芳香化酶抑制剂（AI）广泛用作绝经后女性雌激素受体阳性乳腺癌的辅助治疗。AI已被证明具有等于或更大的疗效和毒性低于他莫昔芬（TAM），多年来的药物选择。依西美坦（EXE）是一种第三代AI，已证明其在治疗乳腺癌患者中具有疗效，与TAM和其他AI一样，对EXE的总体应答和对其他AI的个体间差异相当大。 毒性的发生，但这种变异性的原因尚未阐明。药物代谢的差异可能是患者之间变异性的来源。参与I期和II期代谢反应的几种酶中存在遗传变异，其中许多可导致酶活性的改变，进而改变对药物的治疗反应。EXE被广泛代谢为原形EXE，在尿液中的含量低于1%，在血浆中的含量为10%。我们已经确定了EXE代谢途径的特点，并确定了在这一过程中最活跃的酶。关键代谢步骤之一是17-酮基还原形成17-二氢胆甾烷（17-OH-EXE），这是一种在体外表现出显著抗芳香酶活性的代谢物，并被UDP-葡萄糖醛酸转移酶（UGT）广泛葡萄糖醛酸化，经尿液排泄。在初步研究中，我们已经表明UGT 2B 17的缺失多态性可能对EXE在肝脏中的分布产生显著影响，从而可能影响其治疗效果。除了17-OH-EXE及其葡萄糖醛酸苷外，还有4种其他的EXE代谢产物，其中两种来自17-OH-EXE。在这些和以前的研究中，观察到不同个体的EXE代谢物形成存在相当大的差异。这些数据强调了了解遗传变异是否会影响个体对药物的反应的重要性。我们的假设是，EXE代谢是EXE代谢谱个体间差异的重要来源，EXE代谢酶的多态性在影响EXE治疗效果和毒性方面发挥作用。本提案的具体目的是，（1）表征EXE代谢途径并确定在EXE代谢中具有活性的酶中功能多态性的体外效应，（2）建立EXE代谢谱动力学并确定UGT 2B 17缺失基因型和尿EXE代谢谱之间是否存在体内相关性，以及（3）确定代谢酶基因型之间是否存在相关性，使用NCIC CTG MAP.3试验的样本和临床数据，在大量服用EXE的女性中研究血清EXE代谢产物谱和EXE诱导的毒性和不良事件，该试验正在研究EXE在化学预防和风险降低方面的作用。总之，这些研究将使我们能够充分表征EXE代谢酶途径中的功能相关多态性，这些多态性在EXE临床疗效中具有潜在的重要性。