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Drug-induced kidney injury (DIKI) refers to kidney damage resulting from the administration of medications. The aim of this project was to identify reliable urinary microRNA (miRNAs) biomarkers that can be used as potential predictors of DIKI before disease diagnosis. This study quantified a panel of six miRNAs (miRs-210-3p, 423-5p, 143-3p, 130b-3p, 486-5p, 193a-3p) across multiple time points using urinary samples from a previous investigation evaluating effects of a nephrotoxicant in cynomolgus monkeys. Exosome-associated miRNA exhibited distinctive trends when compared to miRNAs quantified in whole urine, which may reflect a different urinary excretion mechanism of miRNAs than those released passively into the urine. Although further research and mechanistic studies are required to elucidate how these miRNAs regulate signaling in disease pathways, we present, for the first time, data that several miRNAs displayed strong correlations with histopathology scores, thus indicating their potential use as biomarkers to predict the development of DIKI in preclinical studies and clinical trials. Also, these findings can potentially be translated into other non-clinical species or human for the detection of DIKI.
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Biomarcadores , Macaca fascicularis , MicroRNAs , Animais , MicroRNAs/urina , MicroRNAs/genética , Biomarcadores/urina , Masculino , Rim/efeitos dos fármacos , Rim/patologia , Rim/metabolismo , Exossomos/genéticaRESUMO
Microphysiological systems (MPS) are comprised of one or multiple cell types of human or animal origins that mimic the biochemical/electrical/mechanical responses and blood-tissue barrier properties of the cells observed within a complex organ. The goal of incorporating these in vitro systems is to expedite and advance the drug discovery and development paradigm with improved predictive and translational capabilities. Considering the industry need for improved efficiency and the broad challenges of model qualification and acceptance, the International Consortium for Innovation and Quality (IQ) founded an IQ MPS working group in 2014 and Affiliate in 2018. This group connects thought leaders and end users, provides a forum for crosspharma collaboration, and engages with regulators to qualify translationally relevant MPS models. To understand how pharmaceutical companies are using MPS, the IQ MPS Affiliate conducted two surveys in 2019, survey 1, and 2021, survey 2, which differed slightly in the scope of definition of the complex in vitro models under question. The surveys captured demographics, resourcing, rank order for organs of interest, compound modalities tested, and MPS organ-specific questions, including nonclinical species needs and cell types. The major focus of this manuscript is on results from survey 2, where we specifically highlight the context of use for MPS within safety, pharmacology, or absorption, disposition, metabolism, and excretion and discuss considerations for including MPS data in regulatory submissions. In summary, these data provide valuable insights for developers, regulators, and pharma, offering a view into current industry practices and future considerations while highlighting key challenges impacting MPS adoption. SIGNIFICANCE STATEMENT: The application of microphysiological systems (MPS) represents a growing area of interest in the drug discovery and development framework. This study surveyed 20+ pharma companies to understand resourcing, current areas of application, and the key challenges and barriers to internal MPS adoption. These results will provide regulators, tech providers, and pharma industry leaders a starting point to assess the current state of MPS applications along with key learnings to effectively realize the potential of MPS as an emerging technology.
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Indústria Farmacêutica , Sistemas Microfisiológicos , Animais , Humanos , Descoberta de DrogasRESUMO
In May 2022, there is an International Regulatory and Pharmaceutical Industry (Innovation and Quality [IQ] Microphysiological Systems [MPS] Affiliate) Workshop on the standardization of complex in vitro models (CIVMs) in drug development. This manuscript summarizes the discussions and conclusions of this joint workshop organized and executed by the IQ MPS Affiliate and the United States Food and Drug Administration (FDA). A key objective of the workshop is to facilitate discussions around opportunities and/or needs for standardization of MPS and chart potential pathways to increase model utilization in the context of regulatory decision making. Participation in the workshop included 200 attendees from the FDA, IQ MPS Affiliate, and 26 global regulatory organizations and affiliated parties representing Europe, Japan, and Canada. It is agreed that understanding global perspectives regarding the readiness of CIVM/MPS models for regulatory decision making and potential pathways to gaining acceptance is useful to align on globally. The obstacles are currently too great to develop standards for every context of use (COU). Instead, it is suggested that a more tractable approach may be to think of broadly applicable standards that can be applied regardless of COU and/or organ system. Considerations and next steps for this effort are described.
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In drug discovery, during the lead optimization and candidate characterization stages, novel small molecules are frequently evaluated in a battery of in vitro pharmacology assays to identify potential unintended, off-target interactions with various receptors, transporters, ion channels, and enzymes, including kinases. Furthermore, these screening panels may also provide utility at later stages of development to provide a mechanistic understanding of unexpected safety findings. Here, we present a compendium of the most likely functional and pathological outcomes associated with interaction(s) to a panel of 95 kinases based on an extensive curation of the scientific literature. This panel of kinases was designed by AbbVie based on safety-related data extracted from the literature, as well as from over 20 years of institutional knowledge generated from discovery efforts. For each kinase, the scientific literature was reviewed using online databases and the most often reported functional and pathological effects were summarized. This work should serve as a practical guide for small molecule drug discovery scientists and clinical investigators to predict and/or interpret adverse effects related to pharmacological interactions with these kinases.
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Descoberta de Drogas , Bases de Dados FactuaisRESUMO
INTRODUCTION: Secondary pharmacology profiling is routinely applied in pharmaceutical drug discovery to investigate the pharmaceutical effects of a drug at molecular targets distinct from (off-target) the intended therapeutic molecular target (on-target). Data from a randomized, placebo-controlled clinical trial, the APPROVe (Adenomatous Polyp Prevention on VIOXX, rofecoxib) trial, raised significant concerns about COX-2 inhibition as a primary or secondary target, shaping the screening and decision-making processes of some pharmaceutical companies. COX-2 is often included in off-target screens due to cardiovascular (CV) safety concerns about secondary interactions with this target. Several potential mechanisms of COX-2-mediated myocardial infarctions have been considered including, effects on platelet stickiness/aggregation, vasal tone and blood pressure, and endothelial cell activation. In the present study, we focused on each of these mechanisms as potential effects of COX-2 inhibitors, to find evidence of mechanism using various in vitro and in vivo preclinical models. METHODS: Compounds tested in the study, with a range of COX-2 selectivity, included rofecoxib, celecoxib, etodolac, and meloxicam. Compounds were screened for inhibition of COX-2 vs COX-1 enzymatic activity, ex vivo platelet aggregation (using whole blood from multiple species), ex vivo canine femoral vascular ring model, in vitro human endothelial cell activation (with and without COX-2 induction), and in vivo cardiovascular assessment (anesthetized dog). RESULTS: The COX-2 binding assessment generally confirmed the COX-2 selectivity previously reported. COX-2 inhibitors did not have effects on platelet function (spontaneous aggregation or inhibition of aggregation), cardiovascular parameters (mean arterial pressure, heart rate, and left ventricular contractility), or endothelial cell activation. However, rofecoxib uniquely produced an endothelial mediated constriction response in canine femoral arteries. CONCLUSION: Our data suggest that rofecoxib-related cardiovascular events in humans are not predicted by COX-2 potency or selectivity. In addition, the vascular ring model suggested possible adverse cardiovascular effects by COX-2 inhibitors, although these effects were not seen in vivo studies. These results may also suggest that COX-2 inhibition alone is not responsible for rofecoxib-mediated adverse cardiovascular outcomes.
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Doenças Cardiovasculares , Anel Vascular , Animais , Cães , Humanos , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Ciclo-Oxigenase 2 , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/tratamento farmacológico , Fatores de Risco , Fatores de Risco de Doenças Cardíacas , Preparações Farmacêuticas , Anti-Inflamatórios não Esteroides/efeitos adversosRESUMO
The evaluation of toxicity in preclinical species is important for identifying potential safety liabilities of experimental medicines. Toxicology studies provide translational insight into potential adverse clinical findings, but data interpretation may be limited due to our understanding of cross-species biological differences. With the recent technological advances in sequencing and analyzing omics data, gene expression data can be used to predict cross species biological differences and improve experimental design and toxicology data interpretation. However, interpreting the translational significance of toxicogenomics analyses can pose a challenge due to the lack of comprehensive preclinical gene expression datasets. In this work, we performed RNA-sequencing across four preclinical species/strains widely used for safety assessment (CD1 mouse, Sprague Dawley rat, Beagle dog, and Cynomolgus monkey) in â¼50 relevant tissues/organs to establish a comprehensive preclinical gene expression body atlas for both males and females. In addition, we performed a meta-analysis across the large dataset to highlight species and tissue differences that may be relevant for drug safety analyses. Further, we made these databases available to the scientific community. This multi-species, tissue-, and sex-specific transcriptomic database should serve as a valuable resource to enable informed safety decision-making not only during drug development, but also in a variety of disciplines that use these preclinical species.
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Safety related drug failures continue to be a challenge for pharmaceutical companies despite the numerous complex and lengthy in vitro assays and in vivo studies that make up the typical safety screening funnel. A lack of complete translation of animal data to humans can explain some of those shortcomings. Differences in sensitivity and drug disposition between animals and humans may also play a role. Many gaps exist for potential target tissues of drugs that cannot be adequately modeled in vitro. Microphysiological systems (MPS) may help to better model these target tissues and provide an opportunity to better assess some aspects of human safety prior to clinical studies. There is hope that these systems can supplement current preclinical drug safety and disposition evaluations, filling gaps and enhancing our ability to predict and understand human relevant toxicities. The International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) MPS Affiliate is a group of pharmaceutical industry scientists who seek to expedite appropriate characterization and incorporation of MPS to potentially improve drug safety assessment and provide safer and more effective medicines to patients. In keeping with this mission, the IQ MPS Affiliate scientists have prepared a series of organotypic manuscripts for several key drug safety and disposition target tissues (lung, liver, kidney, skin, gastrointestinal, cardiovascular, and blood brain barrier/central nervous system). The goal of these manuscripts is to provide key information related to likely initial contexts of use (CoU) and key characterization data needed for incorporation of MPS in pharmaceutical safety screening including a list of characteristic functions, cell types, toxicities, and test agents (representing major mechanisms of toxicity) that can be used by MPS developers. Additional manuscripts focusing on testing biologically based therapeutics and ADME considerations have been prepared as part of this effort. These manuscripts focus on general needs for assessing biologics and ADME endpoints and include similar information to the tissue specific manuscripts where appropriate. The current manuscript is an introduction to several general concepts related to pharmaceutical industry needs with regard to MPS application and other MPS concepts that apply across the organ specific manuscripts.
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Fígado , Preparações Farmacêuticas , Animais , Barreira Hematoencefálica , Humanos , Rim , PulmãoRESUMO
The human kidney contains approximately one million nephrons. As the functional unit of the kidney, the nephron affords an opportunity to approximate the kidney at a microphysiological scale. Recent emergence of physiologically accurate human tissue models has radically advanced the possibilities of mimicking organ biology and multi-organ combinations in vitro. Anatomically, the nephron is one of the most complex, sequentially integrated microfluidic units in the body making the miniaturized microfluidic systems excellent candidates for capturing the kidney biology in vitro. While these models are promising, there are a number of considerations for practical implementation into a drug development paradigm. Opportunities for pharmaceutical industry applications of new MPS models often start with drug safety testing. As such, the intent of this article is to focus on safety and ADME applications. This article reviews biological functions of the kidney and options for characterizing known roles in nephrotoxicity. The concept of "context-of-use" is introduced as a framework for describing and verifying the specific features of an MPS platform for use in drug development. Overall, we present a perspective on key attributes of microphysiological kidney models, which the pharmaceutical industry could leverage to improve confident safety and ADME evaluations of experimental therapies.
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Rim/efeitos dos fármacos , Preparações Farmacêuticas/metabolismo , Desenvolvimento de Medicamentos , Avaliação Pré-Clínica de Medicamentos/efeitos adversos , Indústria Farmacêutica , Humanos , Dispositivos Lab-On-A-Chip , Técnicas Analíticas Microfluídicas/instrumentação , Modelos Biológicos , Preparações Farmacêuticas/químicaRESUMO
The liver is critical to consider during drug development because of its central role in the handling of xenobiotics, a process which often leads to localized and/or downstream tissue injury. Our ability to predict human clinical safety outcomes with animal testing is limited due to species differences in drug metabolism and disposition, while traditional human in vitro liver models often lack the necessary in vivo physiological fidelity. To address this, increasing numbers of liver microphysiological systems (MPS) are being developed, however the inconsistency in their optimization and characterization often leads to models that do not possess critical levels of baseline performance that is required for many pharmaceutical industry applications. Herein we provide a guidance on best approaches to benchmark liver MPS based on 3 stages of characterization that includes key performance metrics and a 20 compound safety test set. Additionally, we give an overview of frequently used liver injury safety assays, describe the ideal MPS model, and provide a perspective on currently best suited MPS contexts of use. This pharmaceutical industry guidance has been written to help MPS developers and end users identify what could be the most valuable models for safety risk assessment.
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Fígado/metabolismo , Preparações Farmacêuticas/metabolismo , Animais , Avaliação Pré-Clínica de Medicamentos , Indústria Farmacêutica , Humanos , Dispositivos Lab-On-A-Chip , Fígado/química , Preparações Farmacêuticas/química , Medição de RiscoRESUMO
Drug toxicity evaluation is an essential process of drug development as it is reportedly responsible for the attrition of approximately 30% of drug candidates. The rapid increase in the number and types of large toxicology data sets together with the advances in computational methods may be used to improve many steps in drug safety evaluation. The development of in silico models to screen and understand mechanisms of drug toxicity may be particularly beneficial in the early stages of drug development where early toxicity assessment can most reduce expenses and labor time. To facilitate this, machine learning methods have been employed to evaluate drug toxicity but are often limited by small and less diverse data sets. Recent advances in machine learning methods together with the rapid increase in big toxicity data such as molecular descriptors, toxicogenomics, and high-throughput bioactivity data may help alleviate some of the current challenges. In this article, the most common machine learning methods used in toxicity assessment are reviewed together with examples of toxicity studies that have used machine learning methodology. Furthermore, a comprehensive overview of the different types of toxicity tools and data sets available to build in silico toxicity prediction models has been provided to give an overview of the current big toxicity data landscape and highlight opportunities and challenges related to them.
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Big Data , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Aprendizado de Máquina , Animais , Humanos , Relação Quantitativa Estrutura-AtividadeRESUMO
INTRODUCTION: DSM421, a dihydroorotate dehydrogenase inhibitor, was in preclinical development as a potential treatment option for malaria. When tested in a core battery of safety pharmacology assays, DSM421 did not produce any effects at oral doses up to 750â¯mg/kg in an Irwin test in rats, but a respiratory study in rats using head-out plethysmography resulted in substantial changes in respiratory function as well as moribundity and mortality at that and lower doses. An investigation was performed to determine the source of this discrepancy. METHODS: Potential testing errors, differences in types of plethysmography testing chambers, effects on stress indicators, and off-target activity were investigated. RESULTS: Respiratory changes and toxicity (resulting in euthanasia in extremis) were confirmed in a repeat, head-out plethysmography test, but the effects of DSM421 were much less severe overall when the rats were tested in whole-body chambers. Additionally, at the end of the 5-h post-dosing respiratory monitoring periods, levels of stress-related hormones (particularly corticosterone) were higher overall in the head-out, than in the whole-body, tested rats. Furthermore, DSM421 was found to produce changes in cardiovascular function in unrestrained rats, and it was shown to have off-target binding affinity at the adenosine A3 receptor (which is associated with bronchoconstriction). DISCUSSION: The generalized stress inherent to head-out plethysmography testing exacerbated the respiratory effects of DSM421 and was possibly compounded by DSM421's cardiovascular effects, thus artifactually resulting in moribundity and mortality in rats. Care should be taken when choosing whether to use head-out versus whole-body plethysmography chambers during respiratory function testing in animals.
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Antibody-drug conjugates (ADCs) are a promising therapeutic modality for oncology indications. The concept of an ADC platform is to increase the therapeutic index (TI) of chemotherapeutics through more selective delivery of cytotoxic agents to tumor cells while limiting exposure to healthy normal cells. Despite the use of antibodies targeting antigens abundantly and/or exclusively expressed on cancer cells (i.e., target cells), dose limiting toxicities (DLTs) in normal cells/tissues are frequently reported even at suboptimal therapeutic doses. Although advancement of ADC technology has helped to optimize all three key components (i.e., mAb, linker, and payload), DLTs remain a key challenge for ADC development. Mechanisms of ADC toxicity in normal cells/tissues are not clearly understood, but the majority of DLTs are considered to be target-independent. In addition to linker-drug instability contributing to the premature release of cytotoxic drug (payload) in circulation, uptake/trafficking of intact ADCs by both receptor-dependent (FcγRs, FcRn and C-type lectin receptors), and-independent (non-specific endocytosis) mechanisms may contribute to off-target toxicity in normal cells. In this article, we review potential mechanisms of target-independent ADC uptake and toxicity in normal cells, as well as discuss components of ADCs which may influence these mechanisms. This information will provide a deeper understanding of the underlying mechanisms of ADC off-target toxicity and prove helpful toward improving the overall TI of the next generation of ADCs.
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Imunoconjugados/efeitos adversos , Imunoconjugados/farmacocinética , Animais , Transporte Biológico , HumanosRESUMO
Pharmaceutical discovery and development is a long and expensive process that, unfortunately, still results in a low success rate, with drug safety continuing to be a major impedance. Improved safety screening strategies and methods are needed to more effectively fill this critical gap. Recent advances in informatics are now making it possible to manage bigger data sets and integrate multiple sources of screening data in a manner that can potentially improve the selection of higher-quality drug candidates. Integrated screening paradigms have become the norm in Pharma, both in discovery screening and in the identification of off-target toxicity mechanisms during later-stage development. Furthermore, advances in computational methods are making in silico screens more relevant and suggest that they may represent a feasible option for augmenting the current screening paradigm. This paper outlines several fundamental methods of the current drug screening processes across Pharma and emerging techniques/technologies that promise to improve molecule selection. In addition, the authors discuss integrated screening strategies and provide examples of advanced screening paradigms.
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Avaliação Pré-Clínica de Medicamentos/métodos , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/uso terapêutico , Animais , Simulação por Computador , Descoberta de Drogas/métodos , HumanosRESUMO
Most small molecule drugs interact with unintended, often unknown, biological targets and these off-target interactions may lead to both preclinical and clinical toxic events. Undesired off-target interactions are often not detected using current drug discovery assays, such as experimental polypharmacological screens. Thus, improvement in the early identification of off-target interactions represents an opportunity to reduce safety-related attrition rates during preclinical and clinical development. In order to better identify potential off-target interactions that could be linked to predictable safety issues, a novel computational approach to predict safety-relevant interactions currently not covered was designed and evaluated. These analyses, termed Off-Target Safety Assessment (OTSA), cover more than 7,000 targets (~35% of the proteome) and > 2,46,704 preclinical and clinical alerts (as of January 20, 2019). The approach described herein exploits a highly curated training set of >1 million compounds (tracking >20 million compound-structure activity relationship/SAR data points) with known in vitro activities derived from patents, journals, and publicly available databases. This computational process was used to predict both the primary and secondary pharmacological activities for a selection of 857 diverse small molecule drugs for which extensive secondary pharmacology data are readily available (456 discontinued and 401 FDA approved). The OTSA process predicted a total of 7,990 interactions for these 857 molecules. Of these, 3,923 and 4,067 possible high-scoring interactions were predicted for the discontinued and approved drugs, respectively, translating to an average of 9.3 interactions per drug. The OTSA process correctly identified the known pharmacological targets for >70% of these drugs, but also predicted a significant number of off-targets that may provide additional insight into observed in vivo effects. About 51.5% (2,025) and 22% (900) of these predicted high-scoring interactions have not previously been reported for the discontinued and approved drugs, respectively, and these may have a potential for repurposing efforts. Moreover, for both drug categories, higher promiscuity was observed for compounds with a MW range of 300 to 500, TPSA of ~200, and clogP ≥7. This computation also revealed significantly lower promiscuity (i.e., number of confirmed off-targets) for compounds with MW > 700 and MW<200 for both categories. In addition, 15 internal small molecules with known off-target interactions were evaluated. For these compounds, the OTSA framework not only captured about 56.8% of in vitro confirmed off-target interactions, but also identified the right pharmacological targets for 14 compounds as one of the top scoring targets. In conclusion, the OTSA process demonstrates good predictive performance characteristics and represents an additional tool with utility during the lead optimization stage of the drug discovery process. Additionally, the computed physiochemical properties such as clogP (i.e., lipophilicity), molecular weight, pKa and logS (i.e., solubility) were found to be statistically different between the approved and discontinued drugs, but the internal compounds were close to the approved drugs space in most part.
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Hematotoxicity is a significant issue for drug safety and can result from direct cytotoxicity toward circulating mature blood cell types as well as targeting of immature blood-forming stem cells/progenitor cells in the bone marrow. In vitro models for understanding and investigating the hematotoxicity potential of new test items/drugs are critical in early preclinical drug development. The traditional method, colony forming unit (CFU) assay, is commonly used and has been validated as a method for hematotoxicity screening. The CFU assay has multiple limitations for its application in investigative work. In this paper, we describe a detailed protocol for a liquid-culture, microplate-based in vitro hematotoxicity assay to evaluate lineage-specific (myeloid, erythroid, and megakaryocytic) hematotoxicity at different stages of differentiation. This assay has multiple advantages over the traditional CFU assay, including being suitable for high-throughput screening and flexible enough to allow inclusion of additional endpoints for mechanistic studies. Therefore, it is an extremely useful tool for scientists in pharmaceutical discovery and development. © 2018 by John Wiley & Sons, Inc.
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Células da Medula Óssea/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Células-Tronco Hematopoéticas/efeitos dos fármacos , Testes de Toxicidade/métodos , Linhagem da Célula/efeitos dos fármacos , Humanos , Técnicas In Vitro/métodosRESUMO
Gene expression profiling is a useful tool to predict and interrogate mechanisms of toxicity. RNA-Seq technology has emerged as an attractive alternative to traditional microarray platforms for conducting transcriptional profiling. The objective of this work was to compare both transcriptomic platforms to determine whether RNA-Seq offered significant advantages over microarrays for toxicogenomic studies. RNA samples from the livers of rats treated for 5 days with five tool hepatotoxicants (α-naphthylisothiocyanate/ANIT, carbon tetrachloride/CCl4, methylenedianiline/MDA, acetaminophen/APAP, and diclofenac/DCLF) were analyzed with both gene expression platforms (RNA-Seq and microarray). Data were compared to determine any potential added scientific (i.e., better biological or toxicological insight) value offered by RNA-Seq compared to microarrays. RNA-Seq identified more differentially expressed protein-coding genes and provided a wider quantitative range of expression level changes when compared to microarrays. Both platforms identified a larger number of differentially expressed genes (DEGs) in livers of rats treated with ANIT, MDA, and CCl4 compared to APAP and DCLF, in agreement with the severity of histopathological findings. Approximately 78% of DEGs identified with microarrays overlapped with RNA-Seq data, with a Spearman's correlation of 0.7 to 0.83. Consistent with the mechanisms of toxicity of ANIT, APAP, MDA and CCl4, both platforms identified dysregulation of liver relevant pathways such as Nrf2, cholesterol biosynthesis, eiF2, hepatic cholestasis, glutathione and LPS/IL-1 mediated RXR inhibition. RNA-Seq data showed additional DEGs that not only significantly enriched these pathways, but also suggested modulation of additional liver relevant pathways. In addition, RNA-Seq enabled the identification of non-coding DEGs that offer a potential for improved mechanistic clarity. Overall, these results indicate that RNA-Seq is an acceptable alternative platform to microarrays for rat toxicogenomic studies with several advantages. Because of its wider dynamic range as well as its ability to identify a larger number of DEGs, RNA-Seq may generate more insight into mechanisms of toxicity. However, more extensive reference data will be necessary to fully leverage these additional RNA-Seq data, especially for non-coding sequences.
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Acyl glucuronides are important metabolites of compounds with carboxylic acid moieties and have unique properties that distinguish them from other phase 2 metabolites. In particular, in addition to being often unstable, acyl glucuronide metabolites can be chemically reactive leading to covalent binding with macromolecules and toxicity. While there is circumstantial evidence that drugs forming acyl glucuronide metabolites can be associated with rare, but severe idiosyncratic toxic reactions, many widely prescribed drugs with good safety records are also metabolized through acyl glucuronidation. Therefore, there is a need to understand the various factors that can affect the safety of acyl glucuronide-producing drugs including the rate of acyl glucuronide formation, the relative reactivity of the acyl glucuronide metabolite formed, the rate of elimination, potential proteins being targeted, and the rate of aglucuronidation. In this review, these factors are discussed and various approaches to de-risk the safety liabilities of acyl glucuronide metabolites are evaluated.
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Glucuronídeos/metabolismo , Preparações Farmacêuticas/metabolismo , Acilação , Humanos , Microssomos Hepáticos/metabolismo , Modelos Biológicos , SegurançaRESUMO
Most pharmaceutical companies test their discovery-stage proprietary molecules in a battery of in vitro pharmacology assays to try to determine off-target interactions. During all phases of drug discovery and development, various questions arise regarding potential side effects associated with such off-target pharmacological activity. Here we present a scientific literature curation effort undertaken to determine and summarize the most likely functional and pathological outcomes associated with interactions at 70 receptors, enzymes, ion channels and transporters with established links to adverse effects. To that end, the scientific literature was reviewed using an on-line database, and the most commonly reported effects were summarized in tabular format. The resultant table should serve as a practical guide for research scientists and clinical investigators for the prediction and interpretation of adverse side effects associated with molecules interacting with components of this screening battery.