Current Pharmacology Reports最新文献

Purpose of review: Physiologically-based pharmacokinetic (PBPK) modeling is a powerful tool to understand drug movements throughout the human body. Unlike classical PK methods that often lack sufficient physiological detail, PBPK integrates drug-specific properties with organism-specific physiological parameters to predict drug behavior in major body compartments, particularly site of action and providing high physiological realism. The aim of the review is to summarize application of PBPK modeling in drug development and in dietary phytochemicals.

Recent findings: PBPK modeling is a versatile tool in drug development and phytochemical research. It predicts human PK from preclinical data, aiding lead optimization and candidate evaluation. The model mechanistically predicts drug-drug interactions (DDIs), supporting dose adjustments and reducing clinical trials. PBPK also enables formulation simulation for oral and modified-release drugs, optimizing bioavailability and predicting performance from in vitro data, thus reducing costly in vivo studies. Importantly, it extends drug knowledge to pediatric and special populations via virtual group simulations, enabling efficient, cost-effective dosage determination and less clinical trials. For dietary phytochemicals, PBPK modeling is well-suited for their complex mixture and variability. PBPK studies of phytochemicals demonstrate their utility for single components, mixtures, cross-species extrapolation, and complex metabolic processes, although challenges exist.

Summary: PBPK modeling is a dynamic and quantitative tool offering comprehensive pharmacokinetic integration across various populations and regimens. Its importance is growing due to its application at diverse stages of drug development and its ability to adapt to complex substances, including natural products. Ultimately, PBPK modeling is significant for enhancing scientific rigor, expediting drug development and ensuring patient safety.

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Purpose of review: Dietary phytochemicals, bioactive compounds derived from plants, have gained increasing attention for their potential role in cancer prevention. Among these, NRF2 (nuclear factor erythroid 2-related factor 2) activating dietary phytochemicals such as curcumin, sulforaphane, ursolic acid, and cyanidin have demonstrated significant antioxidant and anti-inflammatory properties, making them promising agents in chemoprevention. This review examines the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of these dietary phytochemicals, with a focus on their NRF2-mediated effects in cancer prevention.

Recent findings: Preclinical studies have highlighted the potential of these dietary phytochemicals to modulate oxidative stress and inflammation, key drivers of carcinogenesis. We explore the complexity of their PK/PD properties, influenced by factors such as bioavailability, metabolism, and drug interactions. While most of these phytochemicals follow two compartmental PK, their anti-oxidant and anti-inflammatory effects follow the indirect response (IDR) model. Furthermore, we discuss the application of physiologically based pharmacokinetic (PBPK) modeling to simulate the behavior of these compounds in humans, providing insights for clinical translation.

Summary: The integration of PK-PD analysis into the development of dietary phytochemical-based therapies offers a pathway to optimize dosing strategies, enhance therapeutic efficacy, and improve safety. This review underscores the importance of these compounds as part of cancer interception strategies, particularly in the early stages of cancer development, where they may offer a natural, less toxic alternative to conventional therapies.

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Purpose of review: In this review article, specific emphasis is on evolution of metabolomics in cancer research, metabolomics workflow, general understanding of liquid chromatography - mass spectrometry (LC-MS) based platform for quantitation of metabolites, their biological interpretation and the application in carcinogenesis and cancer prevention by dietary phytochemicals.

Recent findings: Metabolomics is increasingly becoming a preferred approach for next generation metabolic screening and has profound impact on medical practice. Metabolomics describes the end products of biochemical processes which are greatly influenced by genetic and environmental factors. Metabolic alterations can be linked to potential biochemical reactions/enzymes and their corresponding genes. Thus, these results can be further validated via multi-omics approach including genomics, transcriptomics and proteomics. However, challenges exist within and between omic-domain data integration considering complex biochemical regulation including organism versus tissue versus cellular level processes, epigenetics, transcriptional and post translational modifications. Metabolomics can reflect the steady state or dynamic state of metabolism because metabolites are highly dynamic in space and time.

Summary: Metabolomic analysis of biological samples exhibit the possibility to determine mechanism of action of anti-cancer agents, biomarker discovery and impact of genetic alterations.

Tart cherry (TC; Prunus cerasus) has high antioxidant and anti-inflammatory potentials due to its rich bioactive components like anthocyanins, polyphenols, vitamins, beta-carotene, ellagic acid, and chlorogenic acid. Oxidative damage and inflammation are underlying reasons to chronic disease pathogenesis. Oxidative stress usually caused by the imbalance between antioxidants and pro-oxidants. Additionally, a chronic inflammatory state is typically modulated by oxidative stress. Inflammation plays a critical role in chronic health conditions, such as cardiovascular diseases, hypertension, insulin resistance, arthritis and cancer. Numerous studies indicate that there is a strong relationship between TC and the inhibition of inflammation and oxidative damage by regulating different epigenetic and metabolic pathways. In this review, the recent developments of TC components and their metabolites on inflammatory and oxidative damages will be discussed, and the challenges and limitations to better support future research, including clinical trials to confirm these findings.

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Purpose of review: This article outlines the role of mitochondrial dynamics in healthy cells and elaborates on how blood cancer cells hijack these processes to support uncontrolled proliferation, stemness, and drug resistance. A comprehensive understanding of the mechanistic details of mitochondrial behavior in malignant hematopoiesis will provide new therapeutic avenues and improve the prediction of therapy responses.

Recent findings: Mitochondrial dynamics, governed by the complementary events of fusion and fission, is a key cellular process for maintaining metabolic flexibility, organelle integrity, and cellular homeostasis. Impairment of the dynamic fusion-fission balance can lead to various chronic pathologies. Recent research has highlighted how blood cancer cells exploit mitochondrial remodeling to maintain metabolic efficiency and adjust organellar quality control mechanisms to sustain survival pathways and enable cancer progression. Furthermore, leukemia and lymphoma cells use mitochondrial plasticity to adapt under stress conditions and to evade cell death induced by various clinically used or tested therapeutic regimens. Investigations using blood cancer cell lines, patient-derived samples, and xenograft models have begun to uncover the specific roles and regulatory mechanisms of mitochondrial dynamics proteins in different subtypes of hematologic malignancies, as well as in therapy resistance. Additionally, preclinical studies suggest that targeting these regulators may present novel therapeutic opportunities and serve as predictive biomarkers in blood cancers.

Summary: This review highlights the therapeutic potential of modulating mitochondrial dynamics, underscoring the need for further integrative studies to fully harness this vulnerability in hematologic malignancies.

Purpose of review: Acute myeloid leukemia (AML) is a clonal blood neoplasm with dismal prognosis. Despite the introduction of many novel targeted agents, cytotoxic chemotherapy has remained the standard of care for AML. Differences in mitochondrial metabolism between normal and leukemic cells can be targeted by novel AML therapies, but these agents require a comprehensive efficacy and cytotoxicity evaluation.

Recent findings: Metabolic alterations in AML blasts increase their sensitivity to therapies targeting mitochondrial metabolism. Targeting altered mitochondrial metabolism, that is crucial for leukemia cell growth and survival, could be a breakthrough in AML treatment. Therefore, BH3 family proteins, mitochondrial complexes, the tricarboxylic acid cycle, and amino acid (AA) and fatty acid metabolism are common treatment targets in AML. Although many drugs targeting these vulnerabilities showed acceptable safety profiles and promising efficacy in preclinical studies, clinical trials often do not confirm these results limited by narrow therapeutic window. The most effective regimens are based on drug combinations with synergistic or additive activity.

Summary: In this review, we present an overview of the most recent studies targeting mitochondrial metabolism in AML. We highlight that targeting of the specific energy metabolism dependencies of AML blasts provides an opportunity to achieve long-term responses with a reasonable safety profile. We emphasize that currently used drugs and their combinations display dose-limiting toxicities or are not efficient enough to completely eradicate leukemic stem cells. Thus, further studies of complex metabolic rewiring of leukemia cells before and after combinatorial therapies are warranted.