Drug Metabolism Reviews最新文献

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.

Methyldopa, a centrally acting α2-adrenergic agonist, remains a key antihypertensive drug, particularly prescribed for pregnant and renal-impaired patients. Its clinical significance has led to extensive research aimed at developing reliable analytical methods for its accurate, sensitive, and selective determination in pharmaceutical formulations and biological matrices. Relevant literature was retrieved from Scopus, Web of Science, ScienceDirect, PubMed, and Google Scholar, restricted to English-language publications. This review critically examines the diverse analytical approaches used for Methyldopa quantification, outlining their principles, advantages, limitations, and applicability in both advanced and resource-limited settings. Chromatographic methods, especially high-performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC-MS/MS), remain the most robust techniques, offering excellent sensitivity (LOD: 10-50 ng/mL for HPLC; as low as 0.7-15 ng/mL for LC-MS/MS) with rapid analysis times. While LC-MS/MS provides superior detection, it is limited by high costs and technical expertise requirements. Electrochemical methods, particularly voltammetry, stand out for their affordability, rapid analysis, and feasibility in decentralized laboratories, achieving LOD values as low as 0.01-0.05 µM. Spectrophotometric approaches, primarily UV-Vis, remain the simplest and most cost-effective options, making them useful for routine quality control, though with reduced selectivity and higher detection limits. Key analytical challenges include Methyldopa's low concentration in biological fluids, chemical instability, and matrix interferences. This review provides a comparative evaluation of chromatographic, spectrophotometric, and electrochemical techniques, emphasizing the need for portable, low-cost platforms to expand accessibility in therapeutic monitoring. Overall, it offers critical insights for advancing Methyldopa analysis and improving clinical management in diverse healthcare settings.

The gut microbiota (GM), often regarded as a vital 'functional organ,' plays a crucial role in human physiological processes. GM is involved in substance metabolism, especially the biotransformation of pharmaceuticals. It modulates drug pharmacological activity and bioavailability through various metabolic pathways. Since traditional Chinese medicine (TCM) is primarily administered orally, its active compounds inevitably interact with the GM. This review systematically explores the bidirectional interplay between TCM and GM. GM metabolizes TCM components via enzymatic reactions (e.g. hydrolysis, reduction, and deconjugation) and interactions with metabolites, thereby enhancing bioavailability and sometimes modifying pharmacological properties. Conversely, TCM influences GM composition and function by promoting beneficial taxa, restoring microbial balance, and regulating microbial metabolites such as short-chain fatty acids and bile acids. The TCM-GM interaction shows promise in treating chronic diseases, such as inflammatory bowel disease, mental disorders, and cardiovascular diseases. However, challenges remain in fully understanding these interactions due to the complexity of TCM formulations and individual variations in GM composition. Future research should employ multi-omics approaches to develop personalized TCM therapies based on individual GM profiles.