Current drug metabolism最新文献

The brain is highly protected by physiological barriers, in which the blood-brain barrier restricts the entry of most drugs. Intranasal drug delivery is a non-invasive way of drug delivery, which can cross the blood-brain barrier and achieve direct and efficient targeted delivery to the brain. Therefore, it has great potential in application to the treatment of brain diseases. Temperature-sensitive hydrogels undergo a solutiongel transition with temperature change, and the gel form has good mucosal adsorption properties in the nasal cavity, which is commonly used for targeted delivery of drugs for brain diseases. In this article, by introducing the transport mechanism of brain targeting after nasal administration, combined with the prescription design and basic performance study of temperature-sensitive nasal hydrogel, we summarized the research on the role that temperature-sensitive hydrogel plays brain targeting after via nasal administration, aiming to provide a reference for the development of therapeutic drugs for cerebral diseases and their clinical application. A graphical summary.

A majority of the global population suffers from eye diseases, but few effective treatment options are available with ophthalmic drug therapies. The reasons that have been identified are (1) lack of awareness about the options for treatments, drugs, polymeric science, or physiological barriers, (2) limitations in bringing drug therapies to the posterior segment of the eye due to physiological or anatomical limitations, and (3) regulatory and production difficulties of ocular drug products. Innovative ocular medication delivery and therapies are covered in this study, including hydrogels, nano micelles, implants, nanoparticles, microparticles, liposomes, in situ gels, and microneedles. Moreover, due to their potential to capture both hydrophilic and lipophilic medications, increase ocular permeability, prolong the period of residence, enhance drug stability, and increase bioavailability, this review includes nanotechnology-based carriers. The research encompassed various eye disorders, obstacles to ocular delivery, multiple ocular administration routes, a range of nanostructured platforms, characterization approaches, methods to improve ocular delivery, and emerging technologies. This review aims to provide information on the anatomy of the eye, various ocular conditions, and obstacles to ocular delivery. The benefits and drawbacks of various ocular dose forms or delivery techniques are also evaluated. Finally, it describes methods for increasing ocular bioavailability.

Background: The rapid surge in bacterial resistance to classical antibiotics and antimicrobial agents has driven researchers to identify new classes of antimicrobial agents. At the nanoscale, nanotechnological progress has strongly underscored the application of silver and copper since they present high antimicrobial activities toward gram-positive and gram-negative bacteria. Nanostructures containing these two elements-all the more so for hybrid nanocomposites-have been scantily the subject of investigated. The present work aims to develop and study a silver/copper oxide/clay hybrid nanocomposite.

Methods: Nanocomposites of silver, copper oxide, and their hybrid with clay were synthesized via chemical precipitation under controlled pH (9-11) and temperature (60-90°C) conditions. The antibacterial activity was assessed using standard 0.5 McFarland-adjusted bacterial inocula. Characterization was performed using FTIR, XRD, FESEM, and TEM techniques. MIC and MBC were determined through serial dilution, and data were analyzed using one-way ANOVA and Tukey's test (SPSS v26).

Results: The results indicated that the fabricated nanocomposite was impure, with nanosilver particles measuring 30-40 nm and copper oxide particles measuring 200-250 nm. The morphological properties of synthesized Ag/Cu₂O/clay nanocomposites were evaluated using X-ray diffractometer analysis. The minimum inhibitory concentration (MIC) of the hybrid nanocomposite against Staphylococcus aureus and Bacillus subtilis was 1024 μg/ml, and for Escherichia coli and Pseudomonas aeruginosa 2048 μg/ml. The minimum bactericidal concentration (MBC) against Staphylococcus aureus and Bacillus subtilis was 4096 μg/ml, and for Escherichia coli 4096 μg/ml, and Pseudomonas aeruginosa 8192 μg/ml.

Discussion: Silver/copper oxide/clay hybrid nanocomposite exhibited more intensive antibacterial activities towards gram-positive bacteria in the absence of single-component nanocomposites, validating the synergistic effect of silver and copper in aid of clay. Its small efficacy on gram-negative strains also points at the necessity for additional optimization as well as extension. Such outcomes indicate the potential of the hybrid nanocomposite as an aspiring candidate for eventual antimicrobial applications.

Conclusion: These results showed that the antimicrobial property of silver/copper/clay hybrid nanocomposite was better than copper/silver and clay nanocomposite against gram-positive bacteria, while showing a similar effect against gram-negative bacteria.

Moonlighting proteins, defined by their ability to perform distinct, independent functions beyond their primary roles, have garnered attention in metabolic regulation and drug discovery. This review highlights the emerging significance of these proteins in diverse physiological and pathological processes. With examples like glycolytic enzymes and Krebs cycle components, we explore their involvement in transcriptional regulation, immune responses, and stress modulation. Their unique ability to mediate host-pathogen interactions and disease progression underscores their potential as therapeutic targets. Advanced technologies, such as proteomics and bioinformatics, have revolutionized the identification and characterization of these proteins, unraveling their structural and functional complexities. This synthesis aims to bridge gaps in understanding protein multifunctionality and advocates its implications in drug development. By targeting specific functions of moonlighting proteins while preserving their essential roles, new strategies in pharmacology and personalized medicine are envisioned. The review also proposes a roadmap for leveraging these proteins' multifunctionality to address current challenges in therapeutic interventions.

Background: Carboplatin (CP) is a widely used chemotherapeutic agent with poor oral bioavailability and potential systemic toxicity when administered intravenously. There is a growing interest in developing sustained-release oral formulations to improve therapeutic efficacy and patient compliance.

Objective: The present study aimed to develop and evaluate an oral, enteric-coated, PEGylated multi-walled carbon nanotube (MWCNT) formulation (F2) of carboplatin and assess its pharmacokinetic and histopathological profile in comparison with the marketed intravenous product, Kemocarb®.

Methods: A sensitive and robust HPLC method was developed for the quantification of CP in rabbit plasma. Stability studies were performed at 4 °C for 4 hours and -80°C for 4 weeks. Histopathological evaluation was conducted on major organs of mice to assess toxicity. CP and caffeine were extracted with minimal matrix interference. Pharmacokinetic studies were performed following oral administration of the F2 formulation and compared with Kemocarb®.

Results: The developed HPLC method demonstrated good sensitivity, accuracy, and robustness. CP was stable under both short-term and long-term storage conditions. Histological analysis revealed no significant pathological damage in mice organs. The F2 formulation exhibited sustained drug release for up to 24 hours. The Tmax, Cmax, and MRT of CP for F2 were different compared to Kemocarb®, with a relative bioavailability of 1.182 ± 0.24. The Cmax and MRT of F2 were 12.327 ± 0.03* and 3.5805 ± 0.26 h, respectively.

Conclusion: The developed F2 formulation of carboplatin demonstrates sustained release and improved relative bioavailability following oral administration. It may offer a promising alternative to commercial intravenous CP injections (Kemocarb®), potentially supporting metronomic chemotherapy strategies with improved patient compliance and reduced systemic toxicity.

Background: Numerous chronic illnesses, including diabetes, cancer, cardiovascular disease, and neurological disorders, are mostly caused by oxidative stress, which is defined as an imbalance between the body's antioxidant defenses and the generation of reactive oxygen species (ROS). The success of traditional treatments for oxidative stress has been limited because antioxidant medications are not well-absorbed, are quickly broken down, and do not target specific areas of the body.

Methods: Drug delivery methods based on nanotechnology offer a viable solution to these issues by providing therapeutic molecules with improved release characteristics, enhanced bioavailability, and targeted capabilities. Recent developments in nanotechnology have enabled the creation of multipurpose carriers that can simultaneously transmit genes for endogenous antioxidant enzymes and antioxidants.

Results: This integration promotes a long-term healing response and addresses the immediate oxidative stress. Likewise, functionalizing nanocarriers with particular ligands improves localization to oxidative stress locations, including inflammatory tissues or tumor microenvironments, boosting therapeutic efficacy. The potential of nanotherapeutics in reducing oxidative stress-driven diseases is examined in this article.

Discussion: Nanotechnology-based drug delivery approaches offer a novel avenue for the treatment of several oxidative stress-induced diseases. These delivery systems are highly target-specific and have a longer duration of action. Still, more research is needed to address issues, such as safety margins, largescale production, and approval of medicine use.

Conclusion: We address several nanocarrier platforms, such as liposomes, polymeric nanoparticles, dendrimers, and metallic nanoparticles that have proven more effective in delivering therapeutic drugs and antioxidants to specific sites of oxidative damage. Furthermore, nanotherapeutics may enhance their therapeutic potential by protecting these bioactive substances from premature degradation and clearance.

Background: Vincosamide, an indole alkaloid extracted from Nauclea officinalis, exhibits a range of pharmacological activities, such as anti-tumor, antibacterial, and anti-inflammatory properties. However, despite its promising therapeutic applications, there is a notable gap in research focused on the metabolic pathways of vincosamide.

Objectives: This study aims to investigate the metabolism of vincosamide both in vitro and in vivo in rats, and to elucidate its metabolic pathways.

Methods: Samples of liver microsomal incubation, plasma, bile, urine, and feces following vincosamide administration were analyzed by ultra-high performance liquid chromatography-quadrupole-Exactive Orbitraphigh resolution mass spectrometry (UHPLC-Q-Exactive Orbitrap HRMS). The collected data were analyzed using Compound Discovery 3.2 software and the molecular network method. The metabolites identified through these methodologies were subsequently validated using Xcalibur 4.1 software, which provided information on retention times, parent ions, and characteristic fragment ions.

Results: A total of 37 metabolites were identified, including 8 in vitro and 32 in vivo (3 in plasma, 7 in bile, 22 in urine, and 17 in feces). While the metabolism of vincosamide differs in vitro and in vivo in rats, the type of metabolic reaction that occurs is well-defined. The predominant metabolic pathways are oxidation, reduction, deglycosylation, hydration, glucuronidation, methylation, sulfation, glycine conjugation, cysteine conjugation, taurine conjugation, and complex reactions.

Conclusion: This study elucidates the metabolism of vincosamide in vitro and in vivo in rats, thereby expanding the metabolite profile of vincosamide. These findings provide a foundation for the potential development of new drugs based on vincosamide.

Introduction: Lornoxicam is a non-steroidal anti-inflammatory drug belonging to the oxicam class. This study aimed to develop a niosomal gel containing orange oil for improving the anti-inflammatory effect of lornoxicam.

Methods: Lornoxicam-loaded niosomes (LOR-OR-NIO) were prepared using film hydration followed by the sonication method. Particle size, entrapment efficiency, and ex vivo permeation were all considered during the optimization of the niosomal gels by employing the Box-Behnken design. Dermatokinetics and in vivo anti-inflammatory studies were performed using male Wistar rats.

Results: The particle size, entrapment efficiency, and skin permeation ability of the optimized LOR-ORNIO formulation were found to be 354.3 nm, 83.56 %, and 105.63 μg/cm2, respectively. The ex vivo studies indicated that the optimized LOR-OR-NIO gel demonstrated superior drug penetration properties (105.43 μg/cm²) compared to both the LOR-NIO gel (69.23 μg/cm²) and the LOR gel (35.34 μg/cm²). The activation energy values of LOR gel, LOR-NIO gel, and LOR-OR-NIO gel were 2.74 Kcal mol^-1, 1.93 Kcal mol^-1, and 0.94 Kcal mol^-1, respectively.

Discussion: The lower activation energy of the LOR-OR-NIO gel contributed to more skin penetration of the drug. Dermatokinetics investigation demonstrated that the LOR-OR-NIO gel had superior penetration in the epidermal and dermal areas compared to the LOR gel. In vivo anti-inflammatory studies indicated that the LOR-OR-NIO gel exhibited greater edema inhibition compared to both the LOR-NIO gel and LOR gel. These results demonstrated the enhanced anti-inflammatory activity of the LOR-ORNIO gel.

Conclusion: The study concluded that orange oil enhanced skin permeability and influenced the dermatokinetics of the LOR-OR-NIO gel, leading to an improvement in in vivo anti-inflammatory properties.

Venetoclax is a first-in-class B-cell lymphoma/lymphoma-2 (BCL-2) inhibitor that induces apoptosis in malignant cells through the inhibition of BCL-2. The clinical response to venetoclax exhibits heterogeneity, and its sensitivity and resistance may be intricately linked to genetic expression. Pharmacokinetic studies following doses of venetoclax (ranging from 100 to 1200mg) revealed a time to maximum observed plasma concentration of 5-8 hours, with a maximum blood concentration of 1.58-3.89 μg/mL, and a 24-hour area under the concentration-time curve of 12.7-62.8 μg·h/mL. Population-based pharmacokinetic investigations highlighted that factors such as low-fat diet, race, and severe hepatic impairment play pivotal roles in influencing venetoclax dose selection. Being a substrate for CYP3A4, P-glycoprotein, and breast cancer resistance protein, venetoclax undergoes primary metabolism and clearance in the liver, displaying low accumulation in the body.The significance of dose modifications (a 50% decrease with moderate and a 75% reduction with strong CYP3A inhibitors) and a cautious two-hour interval when co-administered with P-glycoprotein inhibitors are highlighted by insights from clinical medication interaction studies. Moreover, an exposure-response relationship analysis indicates that venetoclax exposure significantly correlates not only with overall survival and total response rate but also with the occurrence of ≥ 3-grade neutropenia. In real-world studies, common or severe side effects of venetoclax include tumor lysis syndrome, myelosuppression, nausea, diarrhea, constipation, infection, autoimmune hemolytic anemia, and cardiac toxicity, among others. In this review, we summarize the current clinical pharmacology studies and side effects of venetoclax, which showed that the approved dosage of venetoclax is relatively wide, and the dosage for different hematologic populations can be streamlined in the future.

The well-established calcineurin inhibitor, tacrolimus, as an immunosuppressive agent, is widely prescribed after organ transplantation. Cytochrome P450 (CYP 450) isoforms are responsible for the metabolism of many features associated with food parameters like phytochemicals, juices, and fruits. This review article summarizes the findings of previous studies to help predict the efficacy or side effects of tacrolimus in the presence of food variables. From the commencement of databases associated with the topic of interest to 26 October 2024, all relevant articles were searched through PubMed, Scopus, and Web of Science. The suggested therapeutic range for tacrolimus trough concentration (C₀ ) was reported as 5-15 ng/ml blood. Tacrolimus interaction with food variables could significantly change C₀ after organ transplantation. For example, grapefruit juice could increase tacrolimus C₀ due to CYP enzyme inhibition. Toxicity such as nephrotoxicity could result from turmeric and other herbal or food products. By inhibiting tacrolimus-metabolizing enzymes and transporters, a high intake of vegetables could increase the risk of adverse effects. Secondary metabolites of vegetables could lead to toxicity in patients with tacrolimus. Furthermore, grapefruit juice, citrus fruits, turmeric, and pomegranate juice could change clinical pharmacokinetics parameters such as T_max, C_max, AUC, and C₀ of tacrolimus after organ transplantation. Bioavailability of tacrolimus might be decreased by induction of the CYP450 system and P-gp efflux pump due to cranberry, rooibos tea, and boldo. Increased inhibitory effect on CYP450 system and/or P-gp efflux pump by grapefruit juice, schisandra, berberine, turmeric, pomegranate juice, pomelo, and ginger could increase bioavailability of tacrolimus. A vigilant immunosuppressive strategy accompanied by scheduled therapeutic drug monitoring is recommended before and after transplant surgery.