Drug Metabolism Reviews最新文献

Drug research, particularly in the early discovery phase, increasingly seeks cost-effective and reliable in vitro models to predict drug metabolism. Metalloporphyrins (MPs), due to their structural and functional resemblance to the heme group of cytochrome P450 enzymes (CYP450s), have emerged as versatile biomimetic catalysts for oxidative reactions. This review focuses specifically on metalloporphyrin-based biomimetic catalysis for oxidative drug metabolism studied in scientific papers publishedin the last 10 years (2015-2025). Unlike previous reviews, we highlight the comparative advantages and limitations of MP systems versus enzymatic models (microsomes, recombinant CYP450s), including aspects of selectivity, functional group tolerance, and scalability. We further discuss recent innovations in immobilization strategies, nanostructured supports, and continuous-flow applications that expand MPs' utility in drug metabolism studies. While challenges remain, particularly regioselectivity and oxidation of unactivated C-H bonds, we conclude that MPs serve as complementary tools for metabolite synthesis and mechanistic investigations, and their integration with modern microreactors and peptide-based designs holds promise for future biomimetic drug metabolism research.

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.

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.

CYP24A1 (25-hydroxyvitamin D₃ 24-hydroxylase) functions as the essential catabolic 'off-switch' of the vitamin D endocrine axis. As a mitochondrial cytochrome P450 enzyme, it tightly regulates calcitriol (1,25(OH)₂D₃) levels through a remarkably sensitive negative feedback mechanism, capable of a 20,000-fold transcriptional response-by converting biologically active vitamin D metabolites into the inactive end-product calcitroic acid. Its expression is governed by opposing endocrine cues from Parathyroid Hormone (PTH) and Fibroblast Growth Factor 23 (FGF23), with FGF23-mediated induction of CYP24A1 playing a key role in lowering calcitriol during states of phosphate excess. Pathogenic loss-of-function variants in CYP24A1 underlie Idiopathic Infantile Hypercalcemia (IIH) type 1, whereas acquired dysregulation contributes significantly to chronic kidney disease (CKD). In CKD, sustained FGF23 elevation drives aberrant CYP24A1 activation, promoting functional vitamin D deficiency and secondary hyperparathyroidism. Emerging studies also implicate inflammation-induced CYP24A1 upregulation in metabolic diseases and cancer, establishing it as a molecular basis for vitamin D resistance. The advent of selective CYP24A1 inhibitors represents a promising therapeutic strategy to optimize vitamin D signaling and control hypercalcemia. Incorporating pharmacogenetic markers (e.g. rs2248359) and functional indices such as 24,25(OH)₂D measurements supports individualized vitamin D dosing and advances precision medicine for vitamin D-related disorders.

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.

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.

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.

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.

New drug modalities (NDMs) have gained significant popularity and attention in recent years due to their ability to target previously undruggable pathways and offer new strategies for tackling complex diseases. This trend is reflected in our review, which encompasses 17 publications, an increase from 11 last year and includes a growing number of contributors across industry and academia. We have focused on five categories of NDMs: (1) Peptides with an emphasis on macrocyclic structures; (2) Bivalent protein degraders, also known as proteolysis-targeting chimeras (PROTACs); (3) Conjugated drugs, including peptide-drug and antibody-drug conjugates; (4) Antisense oligonucleotides and N-acetylgalactosamine (GalNAc) conjugated oligonucleotides; and (5) Covalent inhibitors.

This comprehensive review explores the therapeutic promise of cyclodextrin-grafted magnetite (Fe₃O₄) nanocarriers in anticancer applications, focusing on their design, drug delivery mechanisms, biological stability, and therapeutic performance. Systems integrating cyclodextrins (cds) with Fe₃O₄ nanoparticles (Fe₃O₄-cd-drug) have been developed for delivery of key anticancer agents such as docetaxel, irinotecan, paclitaxel, and doxorubicin across 11 cancer cell types. Results demonstrate up to 60% reduced cancer cell viability when using magnetite nanoparticle (Fe₃O₄-np)-cds-docetaxel/irinotecan/doxorubicin systems compared to the pristine drug. cd grafting enhances nanoparticle hydrophilicity, drug encapsulation, colloidal stability, and biocompatibility, enabling sustained and targeted drug release. Direct grafting of cds onto Fe₃O₄ yields superior cytotoxicity of 93% death of epidermoid carcinoma (A431) cells with Fe₃O₄-np-cds-irinotecan system compared to linker-mediated systems. In the case of Fe₃O₄-np-cds-doxorubicin system tested on human breast cancer cell (MCF-7) cells shows 38% cell death and adding hyperthermia kills 30% of cells. Compared to alternative grafting like polyethylene glycol (PEG), poly(lactic-co-glycolic acid) (PLGA), metal-organic frameworks (MOFs), or carbon-based materials, cds offer unique advantages including Food and Drug Administration (FDA)-approved biocompatibility, pH-sensitive release, and support for combination therapies. Cluster analysis categorized Fe₃O₄-cd-drug systems based on cytotoxic efficiency and drug concentration, identifying structure-function relationships and highlighting the superiority of systems with multimodal surface engineering. Mechanistic insights reveal endocytosis-mediated uptake, lysosomal-triggered drug release, reactive oxygen species (ROS) generation via Fenton-like reactions, and enhanced cytotoxicity under hyperthermia. Despite these advances, gaps remain in understanding inclusion complex chemistry, biodistribution, and structure-activity relationships. This review highlights the potential of Fe₃O₄-np-cds-drug systems and emphasizes the urgent need for systematic molecular and material-level studies to optimize Fe₃O₄-cd-drug systems for translational cancer therapy.