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.

项目概要 复方抗生素甲氧苄啶-磺胺甲恶唑 (TMP-SMX) 有效、廉价且广泛使用 处方药，但它也会导致 3-5% 的 TMP-SMX 暴露者出现特殊药物不良反应 (IADR) 患者的使用率远高于大多数其他药物。特别令人担忧的是这些 IADR 正在发生 随着使用量的增加，频率也随之增加。 IADR 令处方者感到恐惧，因为它们可以 导致不可预测的发病率甚至死亡率。尽管存在这些问题，TMP-SMX 仍然是一个关键的 全世界范围内治疗感染的主要疗法，因为几乎没有广泛可用的替代疗法。所以 为了临床开发，有必要增加我们对 TMP-SMX IADR 的机制理解 可以预测风险的相关生物标志物。 尽管 TMP-SMX 是由两种单独药物成分组成的复方抗生素，但 IADR 机制 尽管大量临床证据表明 TMP 有助于这些，但迄今为止的研究仅限于 SMX 不良反应。导致 TMP-SMX IADR 的确切机制尚未阐明；然而， 考虑母体药物对与蛋白质共价结合的化学反应性代谢物的生物活化 成为 IADR 发展的重要启动活动。最近的数据表明，TMP 具有生物活性，可产生反应性 可以与蛋白质共价结合的代谢物。在服用药物的儿童的尿液中发现了 TMP 加合物 TMP-SMX，表明反应性 TMP 中间体在体内形成。目前尚不清楚是否 经历 TMP-SMX IADR 的患者对 SMX 或 TMP 或两者都有反应，因此不可能 确定可能对 TMP-SMX 任一成分引起的 IADR 敏感的潜在患者。 我们假设 TMP 可能是 TMP-SMX 暴露患者中观察到的 IADR 的重要贡献者。 我们将在以下具体目标中解决这一假设：1）确定接受 TMP 治疗的个体是否- SMX 在其循环中含有 TMP 和/或 SMX 蛋白加合物 2) 确定相关的免疫标记物 与每个单独的药物成分相关的 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重要抗生素的临床安全性。这项研究将有助于 有关 TMP-SMX IADR 开发背后机制的关键信息。未来的研究方向将是 开发一种可临床应用的工具来确定风险并增强 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