Current drug metabolism最新文献

Introduction: This review aims to explore the therapeutic potential and safety of herbal biactive compounds in the treatment of various liver disorders. As the liver plays a critical role in digestion, detoxification, energy storage, and protein synthesis, any impairment in its function can lead to significant health complications. The study aims to identify effective herbal agents that may support liver health.

Methods: A comprehensive literature search was conducted using scientific databases and platforms including Web of Science, Scopus, PubMed, HINARI, ScienceDirect, and Google Scholar. The review includes studies that investigate the hepatoprotective potential of herbal bioactives, while research related to hepatic cancers was excluded to maintain a focus on non-malignant liver disorders.

Results: The review identifies several medicinal plants and their active constituents that exhibit hepatoprotective properties. These bioactives function through various pharmacological mechanisms at the molecular level. Common liver conditions addressed include fatty liver, hepatitis, fibrosis, steatosis, and cirrhosis. The reviewed compounds demonstrate antioxidant, anti-inflammatory, and antifibrotic activities, supporting their role in liver disease management.

Discussion: The findings support growing evidence that herbal bioactives can modulate key molecular pathways involved in liver disorders. These results align with existing studies highlighting the benefits of plant-based treatments. However, the limitations include a lack of clinical trial data, poor bioavailability of some compounds, and the need for standardized formulations. Further research is necessary to validate these results in human populations.

Conclusion: Herbal bioactives such as flavonoids, polyphenols, alkaloids, glycosides, saponins, vitamins, and essential oils show promising hepatoprotective effects. This review emphasizes the importance of understanding their precise molecular mechanisms and ADME (absorption, distribution, metabolism, and excretion) profiles. These insights are crucial for developing safe, effective, and standardized herbal therapies for liver disease management.

Background: Cathinone derivatives as new psychoactive substances have attracted worldwide attention in recent years. They have strong excitatory effects on the human central nervous system, which is extremely abusive and harmful. As they are easy to be structurally modified, and rapidly metabolized and excreted after taken, clarifying their metabolic profile is of significant importance to provide useful information for their identification or forensic purposes.

Objective: In this paper, a comparative in vitro metabolic profile study of five cathinone derivatives (4/3/2- methylmethcathinone and 4/3-methoxymethcathinone) was performed, including their metabolic stability in the simulated gastrointestinal tract, mass spectrometry fragmentation behavior, possible metabolic pathways and metabolites in human liver microsomal incubation system, and revealing the key metabolic enzyme isoforms involving in their biotransformation.

Methods: In vitro incubation was performed in simulated gastric/intestinal fluid and human liver microsomes, fragmentation behavior study and metabolite identification were investigated by LC-Q-TOF/MS, and metabolic stability study, along with metabolic enzyme screening were analyzed using LC-MS/MS.

Results: Almost all the cathinone derivatives tested were stable in the simulated gastric/intestinal fluid; characteristic fragmentation pathway and diagnostic fragment ions of the cathinone derivatives were analyzed; the key metabolic pathways of 4/3-methylmethcathinone and 4/3-methoxymethcathinone revealed were hydroxylation and demethylation, which were catalyzed by CYP2D6. The methyl-substituted position would significantly affect the metabolic pathway of the methylmethcathinone.

Conclusion: This study revealed the mass spectral fragmentation pattern and the in vitro metabolic behavior of the selected cathinone derivatives, providing meaningful information and scientific evidence in predicting their metabolic potential in vivo, and also promoting their analysis, detection, and clinical use.

Sickle cell disease (SCD) is a hereditary blood disorder resulting from the production of distorted hemoglobin molecules that cause red blood cells to adopt a sickle or crescent-like shape. This disease affects millions of people, particularly those of African, Mediterranean, Middle Eastern, or South Asian descent. In recent years, however, advancements in the CRISPR-Cas9 gene-editing systems have surged. CRISPR stands for clustered regularly interspaced short palindromic repeats, referring to a specific organization of short, partially repeated DNA sequences in prokaryotic genomes. The CRISPR-Cas9 technique is based on the type II CRISPR system of bacteria and involves the Cas9 nuclease, which is targeted to a particular genome section with the help of single-guide RNA. Initially used for random mutations and small sequence alterations, genome editing methods have advanced to achieve large-scale DNA segment manipulation. The BE and PE-- type CRISPR-Cas9 genome editing variants provide new therapeutic options for genetic disorders, improving patients' prognosis. Curative gene editing using CRISPR-Cas9 technology to correct HBB gene mutations that cause SCD represents a revolutionary therapeutic development. These advances bring new hope to patients with previously untreatable diseases, potentially offering a future where genetic disorders can be addressed at their roots. A major objective of CRISPR technology is to enhance its precision and speed, both critical for effective gene editing. This review focuses on molecular mechanisms of CRISPR-Cas9 technology, CRISPR-- Cas9-based approaches for HBB gene modification, clinical trials, patients with sickle cell disease, and advances in CRISPR technology for sickle cell disease.

Background: BPI-460372 is an orally available, covalent, irreversible small molecule inhibitor of the transcriptional enhanced associate domain (TEAD) 1/3/4, which is currently in clinical development for the treatment of cancers with Hippo pathway alterations.

Objective: This study aimed to determine the cytochrome P450 (CYP) phenotyping, metabolic stability, and in vitro and in vivo metabolic profile of BPI-460372.

Methods: The CYP phenotyping and metabolic stability were assessed by measuring the depletion of substrate. The metabolic profile in hepatocytes and rat and dog plasma was analyzed using ultra-high-performance liquid chromatography combined with Orbitrap tandem mass spectrometry (UHPLC-Orbitrap-HRMS).

Results: BPI-460372 was mainly metabolized by CYP2D6, CYP3A4, and CYP1A2. BPI-460372 exhibited low clearance in human, monkey, and rat hepatocytes, while moderate clearance in dog and mouse hepatocytes. A total of 10 metabolites were identified in five species of hepatocytes, and no human-unique metabolite was detected. In rat plasma and dog plasma, the primary metabolites were M407 (BPI-460430) and M423 (BPI-460456), respectively. The two metabolites were quantitatively determined in rat and dog plasma in pharmacokinetic and toxicological studies. The major metabolic site was 2-fluoro-acrylamide, and major metabolic pathways in hepatocytes, and rat and dog plasma involved oxidative defluorination, hydration, glutathione (GSH) conjugation, hydrolysis, cysteine conjugation, and N-acetyl cysteine conjugation. β-lyase pathway contributed to the metabolism of BPI-460372 in rats to a certain degree.

Conclusion: This study elucidated the metabolism of BPI-460372 and provided a basis for pharmacokinetic and toxicological species selection, human pharmacokinetics prediction, and assessment of clinical co-administration limitations and possible metabolic pathways in humans.

The most significant feature of the high-altitude environment is hypoxia, which affects the activity and expression of drug-metabolizing enzymes and transporters, leading to changes in pharmacokinetic parameters. Notably, gut microbiota is a hidden organ in the body. High-altitude hypoxia will change the composition and quantity of gut microbiota, affect drug metabolism, and change the bioavailability of drugs. This will provide a new perspective on changes in pharmacokinetics at high-altitude. Most studies have revealed that for drugs with low bioavailability and high clearance, the dosage may be increased accordingly. Conversely, the dosage may be reduced to achieve individualized medication. Therefore, this article reviews the changes and mechanisms of drug-metabolizing enzymes, transporters, and gut microbiota in a high-altitude environment and explains the impact of their changes on pharmacokinetics, aiming to provide theories and bases for the adjustment of drug dosage and the rational use of drugs in the clinic under high-altitude environment.

Rifampicin is essential for treating TB. The high incidence of resistance to this drug requires efforts to increase the effectiveness of TB therapy. Immunomodulator supplementation is one effort to overcome this problem. Phyllanthus niruri has an immunomodulating effect, which has been proven to influence the clinical improvement of the immunological profile. However, the effect of this plant on rifampicin's bioavailability should be reviewed to determine potential changes that may affect its antibacterial performance. Several stud-ies have shown an increase in the bioavailability of rifampicin when administered with extracts and active isolates of Carum carvi, Cuminum cyminum, Piper nigrum, and Moringa oleifera through inhibition of the P-gp efflux function in the absorption phase. On the other hand, the decrease occurred in coadministration with Garcinia cola, which activated PXR action and subsequently changed P-gp regulation. Administration of Al-lium sativum and Zingiber officinale extracts did not show significant alteration in bioavailability due to the stimulation of several mechanisms with opposite outputs by each secondary metabolite. In the case of P. niruri supplementation, the potential for a rise in bioavailability could occur due to synergistic effects inhibiting the performance of P-gp, AADAC, and OATP1B. However, the stimulation of PXR and PPARα may reduce or eliminate these effects. Finally, considering that there are so many specific secondary metabolites in P. niruri whose effects on the performance of these functional proteins have not been exposed, in vivo studies are needed to confirm the interactions within complex biological systems.

Piperaquine is an important partner drug in artemisinin-based combination therapy, which is highly effective for the treatment of uncomplicated malaria. Several studies have been reported on its pharmacokinetic profiles in different populations, as well as its bioanalytical methods. Piperaquine shows a very large volume of distribution (up to 877 l/kg), a low oral clearance (0.3-1.9 l/h/kg), and an extremely long terminal elimination half-life (up to 30 days) in both healthy volunteers and malarial patients. Piperaquine metabolism is primarily mediated by CYP3A4, and to a lesser extent by CYP2D6 and CYP2C8. The oral bioavailability of piperaquine can be influenced by the consumption of high-fat food. The pharmacokinetics of piperaquine is affected by body weight, age, and pregnancy. Piperaquine has limited clinically relevant interactions with most commonly prescribed drugs. Plasma has been the most commonly studied matrix, and the most used pretreatment techniques involve protein precipitation. HPLC-UV and HPLC-MS/MS are usually used for the quantification of piperaquine in biological samples with researchers seeking a balance between affordability and sensitivity. This review summarizes the analytical assays used for the quantification of piperaquine in biological samples and its pharmacokinetic properties, with particular attention to information on food-drug interactions, drug-drug interactions, and pharmacokinetic characteristics in special populations, including pregnant women and children.

Background: When managing diabetes, polypharmacy the use of several drugs simultaneously to obtain the best possible glucose control is typical. Drug-drug interactions (DDIs), which can result in side effects and reduced treatment efficacy, have increased.

Objectives: This study evaluated the data mining approach of polypharmacy-based drug-drug interactions for common diabetes medication.

Methods: To identify publications that met the inclusion criteria, several scientific reviews and research papers were searched, including Scopus, Web of Science, Google Scholar, PubMed, Science Direct, Springer Link, and NCBI, using keywords such as diabetes, drug-drug interaction, polypharmacy, data mining, and herbal interaction.

Results: Many important drug-drug interactions among popular anti-diabetic drugs have been identified using data mining. Using iodinated contrast media and metformin together increased the risk of lactic acidosis, and using NSAIDs and sulfonylureas simultaneously increased the risk of hypoglycemia. A higher incidence of DDIs was found in an analysis of elderly individuals and those with several comorbidities. Predictive models have demonstrated high sensitivity and accuracy in detecting possible DDIs from patient and drug data.

Conclusion: Finding and evaluating DDIs in polypharmacy related to diabetes care are made possible through data mining. These results could potentially improve patient safety by influencing more individualized and cautious prescription techniques. The improvement of these methods and their application in standard clinical practice should be the main goal of future studies.

Pancreatic cancer is a highly lethal malignancy with a low 5-year survival rate. This review focuses on natural compounds as potential therapeutics for it. Different types of natural compounds, such as polyphenols, saponins, and alkaloids, have shown anti-pancreatic cancer effects, including inhibiting tumor cell growth, inducing apoptosis, and preventing angiogenesis. They also have indirect impacts on pancreatic cancer through influencing the gut microbiota, glucose and lipid metabolism, and the endocrine system. Additionally, Chinese herbal medicines containing these compounds show promise in clinical applications. However, challenges such as target identification and low bioavailability persist. Future research trends involve interdisciplinary collaboration and the use of advanced technologies to overcome these issues.

Background: Diabetes mellitus, a widespread and chronic metabolic condition, creates significant challenges for healthcare systems due to complications from inadequate glycemic control, patient non-compliance, and the invasive nature of traditional treatments, including oral medications and insulin injections, which often lead to discomfort, variability in blood glucose levels, and low adherence.

Objective: To explore the potential of Transdermal Drug Delivery Systems (TDDS) as a non-invasive and effective alternative for diabetes management, highlighting their advantages, recent technological advancements, and associated challenges.

Methods: This review examines the role of TDDS in diabetes treatment, with an emphasis on recent innovations, including microneedles, hydrogels, and sonophoresis. The study also discusses the benefits of TDDS in maintaining stable plasma drug levels, reducing first-pass metabolism, and integrating with continuous glucose monitoring systems.

Results: Emerging TDDS technologies improve drug permeability, enhance bioavailability, and offer sustained drug release, potentially addressing limitations of conventional delivery methods. However, barriers such as skin permeability, high manufacturing costs, and patient variability remain significant challenges.

Discussion: Multi-drug patches and microneedle-based systems represent innovative approaches that enhance therapeutic efficacy and patient compliance by enabling painless, targeted, and combination drug delivery. With support from nanotechnology and pharmacogenomics, these platforms are evolving toward personalized medicine, offering optimized dosing and reduced side effects.

Conclusion: TDDS presents a promising alternative for diabetes management by improving patient adherence, ensuring controlled drug release, and reducing discomfort associated with injections. While further research is required to overcome existing limitations, advancements in biomaterials and personalized medicine approaches hold the potential to optimize TDDS for widespread clinical application. This research aims to summarize the advancements and address existing challenges for future development.