Trimethoprim: an overlooked contributor of trimethoprim-sulfamethoxazole idiosyncratic adverse drug reactions

甲氧苄啶：甲氧苄啶-磺胺甲恶唑异质药物不良反应的一个被忽视的因素

• 批准号: 10425272
• 负责人: Jennifer Lynn Goldman
• 金额: $ 26.77万
• 依托单位: CHILDREN'S MERCY HOSP (KANSAS CITY, MO)
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10425272
• 关键词: Acetylcysteine; Address; Adverse reactions; Affect; Alcohols; Alleles; Antibiotics; Antibodies; Antigens; Binding; Biological Markers; Blood Circulation; Chemicals; Child; Clinical; Clinical Research; Combined Antibiotics; Cutaneous; Cysteine; Data; Detection; Development; Event; Frequencies; Fright; Future; Genetic; Glutathione; Goals; HLA Antigens; Human; Immune response; Immunization; Immunologic Markers; Immunologics; Immunology; In Vitro; Individual; Infection; Label; Laboratories; Laboratory Research; Liver; Liver Microsomes; Metabolic Activation; Methods; Modeling; Modification; Morbidity - disease rate; Parents; Patients; Pharmaceutical Preparations; Plasma; Post-Translational Protein Processing; Process; Proteins; Proteomics; Publishing; Reaction; Research; Risk; Role; Safety; Site; Skin; Sulfamethoxazole; Sulfate; Symptoms; Testing; Tissues; Translational Research; Trimethoprim; Trimethoprim-Sulfamethoxazole; Urine; Work; adduct; adverse drug reaction; base; clinically relevant; cohort; dermatome; experience; human leukocyte antigen testing; in vivo; innovation; insight; keratinocyte; liver injury; mortality; novel strategies; prospective; public health relevance; sulfotransferase; tool

PROJECT SUMMARY The combination antibiotic trimethoprim-sulfamethoxazole (TMP-SMX) is effective, inexpensive, and widely prescribed, yet it also causes idiosyncratic adverse drug reactions (IADRs) in 3-5% of TMP-SMX exposed patients, a rate much higher than that of most other drugs. Particularly alarming is that these IADRs are occurring with increasing frequency subsequent to increasing use. IADRs are feared by prescribers because they can result in unpredictable morbidity and even mortality. Despite these problems, TMP-SMX remains a critical mainstay therapy for treating infections worldwide because there are few widely available alternatives. Therefore it is essential to increase our mechanistic understanding of TMP-SMX IADRs in order to develop clinically relevant biomarkers that can predict risk. Although TMP-SMX is a combination antibiotic made up of two individual drug components, IADR mechanistic studies have to date been limited to SMX despite considerable clinical evidence that TMP contributes to these undesired reactions. The exact mechanism that leads to TMP-SMX IADRs has yet to be elucidated; however, bioactivation of a parent drug to a chemically reactive metabolite that covalently binds to a protein is considered to be an essential initiating event for IADR development. Recent data shows that TMP is bioactivated to reactive metabolites that can covalently bind to protein. TMP adducts have been identified in the urine of children taking TMP-SMX, suggesting that reactive TMP intermediates are formed in vivo. Currently it is not known whether patients experiencing TMP-SMX IADRs are responding to SMX, or to TMP, or to both, making it impossible to identify prospective patients who might be susceptible to an IADR caused by either component of TMP-SMX. We hypothesize that TMP may be a significant contributor to IADRs observed in TMP-SMX exposed patients. We will address this hypothesis in the following specific aims: 1) determine whether individuals treated with TMP- SMX have TMP and/or SMX protein adducts in their circulation 2) determine immunologic markers associated with TMP-SMX IADRs as related to each individual drug component and 3) determine if TMP metabolites are capable of covalently modifying proteins in the skin. Our long-term goal is to increase the clinical safety profile of this essential antibiotic. This research will contribute critical information about the mechanism behind TMP-SMX IADR development. Future studies will be directed in developing a tool that could be applied clinically to determine risk and enhance safe prescribe of TMP-SMX.

项目总结 甲氧苄氨嘧啶-磺胺甲恶唑(TMP-SMX)是一种有效、廉价、应用广泛的联合抗生素 处方，但它也会导致3%-5%的TMP-SMX暴露的特殊不良反应(IADR) 患者，这一比率远远高于大多数其他药物。尤其令人担忧的是，这些IADR正在发生 随着使用的增加，频率也随之增加。IADR被处方者害怕，因为它们可以 导致不可预测的发病率甚至死亡。尽管存在这些问题，TMP-SMX仍然是一个关键 世界各地治疗感染的主流疗法，因为几乎没有广泛可用的替代疗法。因此 提高我们对TMP-SMX IADRs的机制认识是临床发展的关键 可以预测风险的相关生物标志物。 尽管TMP-SMX是一种由两个单独的药物成分组成的联合抗生素，但IADR机制 到目前为止，研究仅限于SMX，尽管有相当多的临床证据表明TMP对这些 不受欢迎的反应。导致TMP-SMX IADRs的确切机制尚未阐明；然而， 母体药物对与蛋白质共价结合的化学反应代谢物的生物活化被认为是 成为国际药品不良反应发展的重要启动活动。最近的数据表明，TMP是生物活性的 能与蛋白质共价结合的代谢物。在服用TMP的儿童的尿液中发现了TMP加合物 TMP-SMX，表明活性TMP中间体是在体内形成的。目前尚不清楚是否 经历TMP-SMX IADR的患者对SMX、TMP或两者都有反应，使其不可能 确定可能对由TMP-SMX的任何一种成分引起的IADR易感的潜在患者。 我们假设TMP可能是在TMP-SMX暴露患者中观察到的IADRs的重要因素。 我们将在以下具体目标中解决这一假设：1)确定接受TMP治疗的患者- SMX在其循环中有TMP和/或SMX蛋白加合物2)确定相关的免疫标志物 与每个单独药物成分相关的TMP-SMX IADR，以及3)确定TMP代谢物是否 能够共价修饰皮肤中的蛋白质。 我们的长期目标是提高这种基本抗生素的临床安全性。这项研究将对 关于TMP-SMX IADR开发背后的机制的关键信息。未来的研究将定向 正在开发一种可用于临床的工具，以确定风险并增强TMP-SMX的安全处方。

项目成果

Screening Trimethoprim Primary Metabolites for Covalent Binding to Albumin.

• DOI: 10.1007/s00044-020-02570-z
• 发表时间: 2020-07
• 期刊: Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents
• 作者: Nolte WM;Tessman RT;Goldman JL
• 通讯作者: Goldman JL

Simultaneous quantification of trimethoprim metabolites in pediatric plasma.

• DOI: 10.1016/j.jchromb.2022.123232
• 发表时间: 2022-05-15
• 期刊: JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES
• 影响因子: 3
• 作者: Tessman, Robert T.;Nolte, Whitney;Toren, Paul;Gibson, Kim;Vu, Linda;Goldman, Jennifer
• 通讯作者: Goldman, Jennifer