Current drug metabolism最新文献

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.

Objective: This Phase I clinical trial aimed to address the knowledge gap regarding topiroxostat's use outside Japan by characterizing its pharmacokinetic profile, safety, and efficacy in healthy Chinese subjects.

Methods: The trial followed a randomized, open-label, three-dose group design, enrolling 12 healthy participants and administering topiroxostat at three different dose levels. The study utilized NONMEM software for pharmacokinetic analysis, evaluating the impact of demographic and biochemical covariates on drug disposition.

Results: Pharmacokinetic analysis shows the peak drug concentration (Cmax) under a single oral administration of 20, 40, and 80 mg of Topiroxostat, which was found in healthy subjects to be 215.46 ± 94.04 ng/mL, 473.74 ± 319.83 ng/mL and 1009.63 ± 585.98 ng/mL, respectively. The time to peak drug concentration (Tmax) was longer in females (0.79-0.98 h) than in males (0.53-0.93 h). Activated partial thromboplastin time (APTT) and triglycerides (TG) were included as covariates for the typical value of the absorption rate constant (TVKA) in our pharmacokinetic model. The dose (DOSE) was considered a covariate for the typical value of bioavailability (TVF1), and sex (SEX) was considered a covariate for the typical value of clearance (TVCL). The typical population values for topiroxostat included Q/F at 4.91 L/h, KA at 0.657 h-¹, Vc/F at 32.5 L, Vp/F at 30 L, and CL/F at 124 L/h.

Conclusion: The trial successfully established the pharmacokinetic parameters of topiroxostat in a Chinese population, confirming its safety and efficacy. The results support the need for individualized dosing strategies and optimize therapeutic outcomes.

Objective: Timosaponin AIII, with poorly soluble characteristics, has a potential antidiabetic effect evaluated in vitro and in vivo. The major problem associated with poorly soluble drugs is very low bioavailability. This study aimed to investigate the metabolic profiles and antidiabetic mechanism of Timosaponin AIII.

Materials and methods: The metabolic profiles of Timosaponin AIII in intestinal flora were analyzed using LC-MS/MS. Based on mass spectrometry analysis, network pharmacology combined with the GEO database was used to identify potential targets and elucidate the antidiabetic mechanism. Finally, the stability of compound- target complexes was further functionally confirmed by molecular docking.

Results: As a result, 13 metabolites were identified. After the compound-target network, the genes of its metabolites increased by 60 compared to those of Timosaponin AIII. Subsequently, 13 core targets related to antidiabetic efficacy were identified through PPI network analysis. Key genes EGFR, MAPK1, and ICAM1 with strong binding efficiencies with metabolites were identified as crucial targets for the therapeutic effects of Timosaponin AIII. The KEGG analysis indicated that timosaponin AIII combated diabetes through various signaling pathways, including PI3K-Akt, FoxO, and HIF-1 signaling pathways, etc. Conclusion: Taken together, this study clarified the mechanism of Timosaponin AIII against diabetes by identifying additional targets and pathways, and the importance of glycosidic structures. Otherwise, we might provide a solid foundation for the development of clinical applications of Timosaponin AIII.

Human breast cancer resistance protein (BCRP, gene symbol ABCG2) is an ATP-binding cassette (ABC) efflux transporter that is highly expressed on the apical membranes of intestinal epithelium and contributes to the absorption, distribution, and elimination of xenobiotics and the efflux of endogenous molecules. Also, the intestinal epithelial monolayer is the largest interface and the most important functional barrier between the internal environment and the systemic circulation. Extensive studies have demonstrated that intestinal ABCG2 of humans and rodents plays a crucial role in limiting absorption of xenobiotics, which are ABCG2 transport substrates, in the small intestine by mediating distribution in the intestinal epithelial barrier. Therefore, changes in the expression, function and activity of ABCG2 in the intestinal epithelial barrier play important roles in drug response and side effects. In this review, we specifically summarize the current research progress of ABCG2 in intestinal drug transport, intestinal urate excretion and intestinal barrier dysfunction, and its role in altering the intestinal epithelial barrier permeability in human intestinal disorder.

Objective: Di-2-ethylhexylphthalate (DEHP) is utilized as a plasticizer in polyvinylchloride products (PVC). When medical devices like blood bags, tubes, and syringes are employed, DEHP leaches out of the PVC polymers and enters biological fluids through non-covalent binding. The presence of DEHP in peripheral blood leads to contamination of bone marrow. Previous research has demonstrated that this chemical induces oxidative stress, which adversely affects the viability and osteo-differentiation of bone marrow mesenchymal stem cells (BMSCs). Hence, our current study aims to utilize gallic acid (GA), a natural antioxidant, to alleviate the inhibitory effects of DEHP on BMSCs' osteogenic differentiation.

Materials and methods: In osteogenic media, BMSCs extracted from Wistar rats were treated with 0.25 μM of GA and 100 μM of DEHP individually and in combination for 20 days. Then viability, total protein, malondialdehyde (MDA), total antioxidant capacity (TAC), catalase (CAT) and superoxide dismutase (SOD), alkaline phosphatase activity, production of collagen1A1 protein as well as expression of Bmp2 and 7, Smad1, Runx2, Oc, Alp, Col-1a1 genes were investigated.

Results: The viability and differentiation ability of BMSCs was significantly (p<0.0001) decreased by DEHP, while GA significantly (P<0.0001) ameliorated the effect of DEHP. DEHP caused a significant decrease (P<0.0001) in the total protein and collagen-1A1 concentration, TAC and activity of antioxidant enzymes, but significantly (P<0.001) increased MDA level. In addition, DEHP caused a significant decrease in the expression of osteo-related genes. In the co-treatment group, GA mitigated the toxic effects of DEHP compared to the control group by inhibiting DEHP-induced oxidative stress and enhancing cell viability and osteo-differentiation properties.

Conclusion: These results confirm that GA reduces the negative effects of DEHP on the osteo-differentiation of BMSCs at the cellular level. However, further studies are necessary to validate these findings.