Drug Metabolism Reviews最新文献

Multidrug resistance remains a major challenge in cancer therapy, arising from complex adaptive mechanisms that enable tumor cells to survive pharmacological stress. Among these mechanisms, redox-regulating enzymes play a pivotal role by maintaining intracellular redox balance and supporting cellular defense systems during chemotherapy. Beyond their classical detoxification functions, redox enzymes critically influence cancer drug metabolism by modulating bioactivation, detoxification efficiency, and NADPH-dependent redox homeostasis. Glutathione-dependent enzymes, NAD(P)H-linked oxidoreductases, and redox-sensitive signaling regulators collectively drive metabolic reprogramming and stress tolerance in drug-treated cancer cells. Rather than acting as isolated determinants of drugresponse, these enzymes function as interconnected and adaptive networks that dynamically respond to therapeutic pressure. Such network-level organization enables compensatory mechanisms that promote metabolic flexibility and reduced treatment response.This review highlights how redox enzyme networks shape cancer drug metabolism and treatment outcomes, emphasizing their implications for drug clearance, metabolic adaptation, and treatment efficacy. Understanding these systems from a network-based perspective may provide a conceptual foundation for metabolism-aware therapeutic strategies aimed at overcoming drug resistance.

Spironolactone (SPI) is a synthetic aldosterone antagonist steroid used to treat various conditions, including hypertension, heart failure, primary hyperaldosteronism, and androgen-related disorders. SPI undergoes extensive hepatic metabolism via cytochrome P450 to active derivatives, including canrenone. Accurate determination of SPI and derivatives is important for pharmacokinetic profiling, therapeutic drug monitoring, pharmaceutical quality control, and environmental monitoring. However, spiking of analyte concentration, chemical instability, matrix complexity, and low analyte levels, which require more sensitive instrumentation, present challenges for analytical determination. Although several methodologies, including spectrophotometric, chromatographic, and electroanalytical techniques, have been reported in the last thirty years, high-performance liquid chromatography (HPLC) and particularly HPLC coupled with tandem mass spectrometry (LC-MS/MS) is the most robust, sensitive, and flexible of these methods for measuring SPI and its metabolites in various matrices. In addition, several sample-preparation techniques, such as Protein Precipitation (PP), liquid-liquid extraction (LLE), and solid-phase extraction (SPE), have been applied with HPLC or LC-MS/MS to enhance analytical performance by minimizing interferences from the complex matrix. This review critically evaluates measurement methodologies in the literature for SPI, focusing on their development, advantages, and disadvantages, and emerging trends toward rapid, inexpensive, and miniaturized platforms. Based on its analytical performance, reproducibility, and applicability, LC-MS/MS (and HPLC)-based methodology is the most suitable for comprehensive SPI analysis.

Doxorubicin, an anthracycline antibiotic extensively used in cancer treatment, is limited by its dose-dependent cardiotoxicity caused by oxidative stress, mitochondrial dysfunction, inflammation, and cardiomyocyte apoptosis-ultimately leading to cardiomyopathy, heart failure, and decreased quality of life. Although dexrazoxane is the only FDA-approved cardioprotective agent, concerns about its long-term safety and potential interference with doxorubicin's antitumor effectiveness have increased the search for safer alternatives. This study investigates the cardioprotective effects of phytochemicals and herbal compounds that target key signaling pathways involved in doxorubicin-induced cardiotoxicity, specifically PI3K/Akt, AMPK/SIRT1, Nrf2/Keap1, NF-κB, and Akt/mTOR/GSK-3β. Despite promising preclinical evidence of their antioxidant, anti-inflammatory, and anti-apoptotic properties, the clinical use of phytochemicals is limited by issues such as low bioavailability, poor specificity, dose-dependent toxicity, variable pharmacokinetics, and lack of standardization. Therefore, innovative approaches-such as ligand-targeted delivery systems, nanotechnology-based formulations, and structural modifications of lead compounds-are essential to enhance their pharmacological properties, safety, and therapeutic effectiveness for effective cardioprotection against doxorubicin-induced toxicity.

The pursuit of precision in anesthesiology is persistently challenged by profound and unpredictable inter-patient variability in drug response. While pharmacogenomics has provided critical insights, a significant portion of this variability remains unexplained. Emerging evidence now positions the gut microbiota as a central, dynamic regulator of perioperative pharmacology. This review introduces and explores the concept, used here as a working label, of the anesthetic pharmacomicrobiome, defined as the set of microbial-host interactions that may influence perioperative drug disposition and effect. We adopt this descriptive shorthand for clarity. We synthesize evidence demonstrating how gut microbes clearly directly metabolize some perioperative drugs (for example opioids), and how other agents (for example propofol) have biologically plausible microbe-related interactions (propofol glucuronidation and potential microbial β-glucuronidase-mediated reactivation) that remain to be demonstrated in direct clinical studies; hypothesis-driven statements are labeled as 'Hypothesis/Speculative'. Furthermore, we detail how the perioperative period itself, through fasting, antibiotics, opioids, and surgical stress, assaults this microbial ecosystem, creating a vicious cycle of dysbiosis that amplifies risk for adverse outcomes like prolonged sedation, postoperative delirium, and chronic pain. Finally, we outline a translational roadmap, advocating for microbiome-based diagnostics, targeted therapeutic interventions, and integrated dosing models to usher in a new era of precision, microbiome-informed perioperative care.

Idiosyncratic drug reactions (IDRs)represent a major risk for drug development. Current methods do not reliably predict IDR risk. There is strong evidence that most IDRs are immune-mediated. An adaptive immune response requires 2 signals: signal 1 represents recognition of drug-related antigens by T cell receptors presented in the context of HLA, and signal 2 represents upregulation of co-stimulatory molecules on antigen-presenting cells (APCs). There is circumstantial evidence that most IDRs are caused by reactive metabolites. Reactive metabolites have the potential to provide both signal 1 and signal 2. Covalent binding studies have been used to try to predict IDR risk, especially liver injury, but the results have been far from perfect with many safe drugs leading to high covalent binding. That begs the question of what reactive metabolite characteristics are associated with IDR risk. Likely characteristics associated with risk include dose, transporters that concentrate the drug in the liver, the enzyme that formed the reactive metabolite, the reactivity of the metabolite, and how it is presented to the immune system. For example, some drugs are bioactivated by myeloperoxidase, which is present in neutrophils and APCs. Not only is this associated with the risk of agranulocytosis, but it also can lead to activation of APCs and upregulation of signal 2. Unlike signal 1, which requires specific HLA molecules and T cell receptors, signal 2 is unlikely to be idiosyncratic. There is evidence that release of damage-associated molecular pattern molecules (DAMPs) and activation of APCs are better predictors of IDR risk.

Antibody-based therapeutics are specifically designed to bind to antigens, thereby facilitating the treatment of various diseases, including tumors and autoimmune disorders, resulting in significant therapeutic effects. Notably, the therapeutic efficacy of antibody-based therapeutics is contingent upon their in vivo processes. This article provides a review of the pharmacokinetic and biological analysis methods for antibody-based therapeutics, encompassing their absorption, distribution, and elimination within the organism. The analysis reveals that antibody-based therapeutics are predominantly administered intravenously or subcutaneously and undergo distribution within organs primarily through convection. The principal mechanisms for drug clearance include targeted clearance and endocytosis. Furthermore, many antibody-based therapeutic formulations are implantations of strategies aimed at extending their half-lives. These critical findings offer valuable insights and foundational knowledge for the research and development of the in vivo processes related to antibody-based therapeutics.

Herbal medicines are widely used worldwide, often alongside prescription drugs, creating the potential for clinically significant herb-drug interactions. These interactions are frequently mediated by effects on drug-metabolizing enzymes (DMEs), particularly those of the cytochrome P450 (CYP450) family, as well as phase II conjugation pathways. This review examines current evidence on how selected herbal extracts influence key enzymes such as cytochrome P450 family 3 subfamily A member 4 (CYP3A4), cytochrome P450 family 2 subfamily D member 6 (CYP2D6), cytochrome P450 family 2 subfamily C member 9 (CYP2C9), and UDP-glucuronosyltransferases (UGTs), and highlights the implications for drug safety and efficacy. Major findings from the literature indicate that herbs like St. John's Wort, Ginkgo biloba, and turmeric can either inhibit or induce enzyme activity, leading to altered drug metabolism. However, results vary widely due to differences in extract composition, dosage, study design, and genetic factors among populations. It is important to note that there remains less clinical evidence as compared to in vitro or animal data, which makes it necessary to be careful when interpreting the results. In addition to pharmacokinetic interactions, this review discusses potential toxicity concerns and safety risks linked to the use of herbal medicinal products. It also outlines key challenges in effectively monitoring and regulating their safe use in clinical practice. Investigating, standardizing herbal product quality, improving study methodologies, and integrating pharmacogenomic data will be essential steps toward ensuring patient safety when combining herbal and conventional therapies.

Chemoresistance remains a major barrier in cancer therapy, frequently resulting in treatment failure and reduced patient survival. This multifaceted phenomenon arises from the interplay of well-established mechanisms such as genetic mutations, non-genetic adaptations, and tumor microenvironment (TME) mediated influences as well as newly emerging findings from recent research (2020-present). Key biochemical contributors include diminished intracellular drug accumulation through altered uptake or efflux, dysregulation of drug metabolism and bioactivation involving multiple Phase I and Phase II enzymes, genomic instability affecting DNA repair pathways, disruption of cell cycle control, and evasion of apoptosis. In addition, recent evidence highlights the roles of epigenetic reprogramming, metabolic reconfiguration, and TME-derived signaling in amplifying chemoresistance. This review integrates both foundational concepts and recent advancements in understanding drug resistance, with particular emphasis on updated insights into drug-metabolizing enzymes and their impact on therapeutic failure. It also evaluates current and emerging strategies to overcome resistance including targeting metabolic enzymes, modulating the TME, and implementing polytherapy's that address multiple resistance pathways. By synthesizing established knowledge with recent discoveries, this review highlights promising directions for improving the efficacy of cancer treatments and enhancing patient outcomes.

Pregnane X receptor (PXR; NR1I2) is a promiscuous ligand-activated nuclear receptor traditionally recognized as a master regulator of xenobiotic detoxification. Beyond xenobiotic detoxification, emerging evidence implicates PXR as a pivotal regulator of both cholesterol and bile acid metabolism, integrating sterol balance with detoxification pathways. While bile acid regulation by PXR is well established, its contribution to dyslipidemia and cardiovascular risk remains an emerging area of translational relevance. Mechanistically, PXR activation induces CYP3A4 and other phase I/II enzymes, elevating plasma 4β-hydroxycholesterol as a biomarker of receptor activity. Crosstalk with sterol regulatory networks, particularly SREBP2, drives upregulation of HMGCR and PCSK9, enhancing cholesterol synthesis and LDL-C levels. Interactions with LXR and FXR further integrate PXR into sterol and bile-acid signaling loops. Pharmacologic activation by diverse agents-including rifampicin, azoles, antiretrovirals, and herbal products-can disrupt lipid balance, while NR1I2 polymorphisms shape interindividual susceptibility. This review synthesizes mechanistic, pharmacogenomic, and regulatory insights to highlight PXR as both a metabolic liability in polypharmacy and a potential therapeutic target in dyslipidemia and liver disease. This review highlights PXR's dual role at the intersection of bile acid detoxification and cholesterol regulation, clarifying mechanistic, pharmacogenomic, and clinical implications.

Microbial phase II biotransformation, involving conjugation reactions such as glycosylation, sulfation, and glucuronidation, is increasingly recognized as a valuable in vitro model for mammalian xenobiotic metabolism, particularly drug metabolism. Fungi, especially Cunninghamella species, demonstrate a notable capacity to produce conjugated metabolites, while bacteria also contribute to this process. Although microbial pathways often parallel mammalian metabolism, key differences exist - for example, glycosylation predominates in microbes, whereas glucuronidation is more common in mammals. Microbial biotransformation enables the production of novel and rare metabolites with potentially enhanced pharmacological properties and provides an efficient, eco-friendly alternative to complex chemical synthesis. Furthermore, microorganisms play a significant role in the detoxification and bioremediation of xenobiotics by increasing solubility and reducing toxicity of harmful compounds. Despite some limitations and discrepancies compared to mammalian systems, microbial models offer valuable tools for drug development, metabolite production, and environmental applications. Continued research into the enzymatic mechanisms, metabolic diversity, and ecological roles of microbial phase II pathways is essential to fully exploit their potential in pharmaceutical and environmental sciences.