Current Drug Metabolism - Online First

Human hepatic carcinoma cell lines are widely used in vitro to study lipid and xenobiotic metabolism, as well as glucose regulation in both normal and diseased states. However, their validity is often questioned due to variability in protein expression compared to primary human hepatocytes (cHH). This study aimed to quantify protein abundance in various hepatic cell lines versus cHH and human liver tissue homogenate (HLT) using a data-independent acquisition-based total protein approach (DIA-TPA). We compared the global proteome from the whole cell homogenates of HepaRG, HepG2, and Huh7 cell lines with that of cHH and HLT.

Proteins in whole cell homogenates were digested in solution using pressure-cycling technology (PCT). DIA was performed via sequential window acquisition of theoretical mass spectra (SWATH-MS), and MS2 spectra were quantified using Spectronaut™, followed by analysis with TPA.

We identified 2715, 2578, 2874, 2717, and 3083 proteins in HepaRG, HepG2, Huh7, cHH, and HLT, respectively, at a 1% FDR. The global proteome of cHH significantly differed from that of the cancer hepatic cell lines. Among the cell lines, the global and ADME protein profile of HepaRG most closely correlated with cHH, with 89 out of 101 ADME proteins identified. Clinically relevant DMEs from the CYP450 family (CYP2C9, CYP2C19, CYP2D6, and CYP3A4) and the UGT family (UGT1A1, UGT1A3, UGT1A6, UGT2B7, and UGT2B15) were quantifiable in human hepatocytes, human liver tissue, and the HepaRG cell line. The Huh7 cell line exhibited a higher abundance of proteins related to gluconeogenesis and glycolysis compared to other groups.

This study highlights the potential of untargeted global proteomics in detecting differences in protein expression among various hepatic cell lines and provides a comprehensive database to inform the choice of the cell line in future studies.

Shenfu decoction (SFD), a Traditional Chinese Medicine formula, is used in clinical emergencies. Its effects on seawater-induced hypothermia remain unclear. This study investigates the therapeutic mechanisms of SFD in improving the survival of hypothermic rats through metabolomics and gut microbiota analysis.

Hypothermia was induced in rats via seawater immersion. The chemical constituents of SFD were analyzed using ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS). Survival time and rates of low-temperature water-immersed rats were assessed. Rat blood samples were obtained for analysis of hematologic parameters, electrolytes, hepatic and renal function, cardiac injury, and inflammatory cytokines. To investigate the potential mechanism underlying the survival-prolonging effect of SFD on seawater-immersed hypothermic rats, untargeted blood metabolomics and gut microbiota profiling were employed for preliminary screening.

UPLC-Q-TOF-MS identified almost 50 compounds in SFD, and 1.35 g/kg SFD significantly extended the survival time of seawater-induced hypothermia rats by 6 hours. After hypothermic seawater immersion, the levels of red blood cells, hemoglobin, hematocrit, as well as serum calcium, phosphorus, blood urea nitrogen, alkaline phosphatase, total protein, cardiac troponin T, and interleukin-6 were significantly increased. However, pretreatment with 1.35 g/kg SFD in rats markedly decreased these parameters. The induction of hypothermic seawater immersion elevated blood glucose, and the administration of SFD exacerbated this increase in rats. Metabolomic analysis revealed elevated levels of valerenic acid and benzoylmesaconine in the SFD group, suggesting the restoration of metabolic homeostasis. This recovery was associated with modulation of the gut microbiota, notably an enhancement of beneficial genera, such as Enterococcus.

The findings demonstrated that SFD significantly prolonged survival in a rat model of seawater-immersion hypothermia. The protective mechanism involved a dual action: mitigating hypothermia-induced organ damage and hematological disturbances, coupled with restoring metabolic homeostasis and modulating gut microbiota. SFD has been found to possess specifically enriched beneficial bacterial genera, linked to the activation of brown adipose tissue and non-shivering thermogenesis. This study has provided initial evidence for a gut microbiota-metabolism axis mediating SFD's protective effect.

SFD prolonged survival in rats with seawater-induced hypothermia, likely by enhancing thermogenesis and regulating lipid metabolism through gut microbiota changes. The findings highlighted the potential of SFD for hypothermia prevention; however, its exact underlying mechanisms require further validation.

This systematic review aimed to identify, evaluate, and critically analyze pharmacokinetic models of vancomycin in adult populations published in PubMed and EMBASE between 2020 and 2024.

Twenty-two studies were included, describing 24 models characterized by substantial heterogeneity in terms of study populations, methodological design, and covariate selection. Most models were developed in Asia and focused on hospitalized patients, particularly those in intensive care units (ICUs). Data from 2150 patients were analyzed, with an average of 93 patients per model.

The models demonstrated high variability in pharmacokinetic parameters, such as vancomycin clearance (Cl) and volume of distribution (Vd), influenced by factors, such as renal function, weight, age, and comorbidities. The meta-analysis conducted on clearance and interindividual variability in clearance (IIV Cl) revealed high heterogeneity among the analyzed studies. The average vancomycin clearance was 4.23 L/h, with higher values observed in neurosurgical, oncohematologic patients, and those with increased renal function. The volume of distribution showed greater variability in obese patients and those undergoing continuous renal replacement therapy. Creatinine clearance (ClCr) was identified as a significant covariate in 66% of the models, while weight was significant in 33%. Other important covariates included age, sex, serum creatinine, serum urea, and the hospital admission unit. The meta-analysis of Cl and IIV Cl showed high heterogeneity among the studies, with I² values of 0.83 for Cl and 0.98 for IIV Cl, indicating substantial variability.

The limitations of this study included the diversity of the analyzed populations, which made it challenging to assess the model's suitability. While the models showed advances in precision, challenges, such as the lack of external validation and discrepancies in dosing recommendations, remain.

This review paper has highlighted the need to validate models in diverse populations and clinical settings to optimize personalized vancomycin therapy in adults. The findings have highlighted the importance of validating or adapting pharmacokinetic models to the specific characteristics of each hospital population.

The currently available therapies for acute lung injury (ALI), including glucocorticoids, protease inhibitors, and heparin, have limited clinical efficacy and are often associated with significant side effects. Cepharanthine (CEP) has demonstrated effectiveness in treating pulmonary diseases, but its clinical application is restricted by low solubility and poor bioavailability. This study aimed to develop mannosylated cepharanthine-loaded polymeric micelles (MA-CEP-PMs) to improve CEP bioavailability and enhance lung-targeted delivery for the treatment of ALI.

The pharmacokinetics of MA-CEP-PMs in rats were assessed using Ultra-Performance Liquid Chromatography Quadrupole Time-of-Flight Mass Spectrometry (UPLC-Q-TOF-MS). Lung-targeting ability was evaluated through tissue distribution studies and near-infrared imaging. In a rat model of ALI induced by lipopolysaccharide (LPS), anti-ALI effects were assessed via general physiological indicators, Enzyme-Linked Immunosorbent Assay (ELISA), and Western blot analysis. Hematoxylin-eosin (HE) staining was used to examine hepatotoxicity and nephrotoxicity of MA-CEP-PMs in normal rats. Cytotoxicity of the mannosylated polyethylene glycol–poly(lactic-co-glycolic acid) copolymer (MA-PEG-PLGA) on NR8383 cells was evaluated using the Cell Counting Kit-8 (CCK-8) assay. Cellular uptake experiments were performed to determine the targeting ability of MA-PEG-PLGA in NR8383 cells, and the effects of MA-CEP-PMs on inflammatory cytokines were analyzed using ELISA.

MA-CEP-PMs significantly increased the AUC and exhibited better lung targeting ability compared to the unmodified micelles (p < 0.01). In the ALI model, MA-CEP-PMs improved the thymus and spleen indices, decreased the lung wet-to-dry weight ratio (p < 0.05), alleviated model animal damage, and inhibited inflammatory factor and nuclear factor-κB (NF-κB)–related protein levels (p < 0.05). MA-CEP-PMs exhibited no significant hepatotoxicity or nephrotoxicity. MA-PEG-PLGA exhibited low toxicity against NR8383 cells and greater cell uptake, indicating stronger targeting of the lung. MA-CEP-PMs also exhibited more potent anti-inflammatory effects.

This study focused on the short-term therapeutic effects of ALI, whereas the clinical management of lung injury often requires long-term intervention. Future research should therefore assess the long-term efficacy of this delivery system in chronic lung injury, along with determining its safety profile and potential impacts on extra-pulmonary organs. While the involvement of the NF-κB pathway in the anti-inflammatory effects has been confirmed, it remains to be deciphered whether mannose modification synergistically regulates other signaling pathways and what the specific intracellular targets of CEP are, which would require further exploration through detailed molecular biology experiments.

The MA-CEP-PMs significantly improved CEP bioavailability and increased lung targeting. They exhibited good safety and had a significant effect on ALI management.

The objective of this study was to investigate the mechanism of anti-cerebral ischemia-reperfusion injury (anti-CIRI) of Ai pian by using the network pharmacology approach combined with serum metabolomics technique based on UPLC-MS.

The cerebral ischemia-reperfusion injury (CIRI) model was established by middle cerebral artery occlusion (MCAO). The therapeutic effect of Ai pian on CIRI rats was evaluated by behavioral test, 2,3,5-triphenyltetrazolium chloride (TTC) staining, Nissl staining, and hematoxylin-eosin (HE) staining. The active compound–potential target–disease network for Ai Pian in the treatment of CIRI was established using network pharmacology methods. Rat serum was detected by the metabolomics technique based on UPLC-MS. A Western blot was used to validate common targets of the network pharmacology approach combined with serum metabolomics.

The process of treating CIRI with Ai Pian involved regulating enzyme, nuclear receptor, and transcription factor activity, managing the inflammatory response, and participating in biofilm composition. Twenty endogenous potential biomarkers were screened and submitted to MetaboAnalyst 6.0 for pathway and enrichment analysis. Four metabolic pathways were identified: butanoate metabolism, fructose and mannose metabolism, alanine, aspartate, and glutamate metabolism, and pyrimidine metabolism. Fructose and mannose metabolism and pyrimidine metabolism were two key pathways. Western blot analysis suggested that DHODH, TYMS, and AKR1B1 may be targets through which therapeutic effects are exerted.

The present study made preliminary predictions on the possible mechanisms of Ai Pian against CIRI. Differential metabolites were screened and identified, and the relevant metabolic pathways potentially affected by Ai Pian were discovered to understand the importance of these markers in health and disease. However, there were also some limitations, further exploration of the molecular mechanisms at the transcriptional level was necessary to make the experimental results more reliable.

This research contributed to the development of Ai pian as an adjunctive drug for treating CIRI and provided a basis for further research on CIRI.

As a long-acting DPP-4 inhibitor administered orally once a week, trelagliptin can address the issues of frequent medication and poor compliance associated with traditional hypoglycemic drugs.

The Hypoxia model in rats was constructed at an altitude of approximately 4300 meters. The plasma concentration of trelagliptin was determined by LC-MS/MS. The biochemical indices and the protein expression levels of P-gp and OCT2 in the kidneys of rats were determined to explain the possible reasons for the pharmacokinetic changes of trelagliptin.

This study demonstrated that the pharmacokinetic parameters of trelagliptin were significantly changed in high-altitude hypoxic environments. Compared with the control group, the AUC, MRT, t1/2, and Vd were remarkably increased during acute and chronic hypoxia, while the CL and Ke were decreased. Additionally, the biochemical indexes and protein expression of P-gp and OCT2 were significantly altered.

The study demonstrated that high-altitude hypoxia significantly altered trelagliptin's pharmacokinetics, slowing clearance, prolonging elimination half-life and residence time, and increasing bioavailability. These changes suggested that the optimal therapeutic dosage of trelagliptin should be reassessed under hypoxic exposure.

Polypharmacy is frequently practiced in the management of schizophrenia due to its chronic nature, recurrent relapses, and associated comorbidities. While combining psychotropic medications may benefit patients with treatment-resistant symptoms, it poses risks such as drug–drug interactions (DDIs), adverse effects, and reduced medication adherence. The absence of uniform prescribing standards further complicates clinical decision-making.

This narrative review was conducted using a scoping methodology. Databases including PubMed, Scopus, and Web of Science were searched for English-language publications from 2000 to 2024. Search terms included “schizophrenia,” “polypharmacy,” “drug–drug interactions,” “clinical outcomes,” and “pharmacogenetics.” Eligible sources included clinical trials, observational studies, systematic reviews, and treatment guidelines. Exclusion criteria were non-English articles, gray literature, and individual case reports.

Polypharmacy is reported in 30–60% of individuals with schizophrenia, especially in institutionalized or treatment-resistant populations. Treatment regimens often involve multiple antipsychotics along with adjunctive antidepressants or mood stabilizers. This approach is associated with increased risks of metabolic syndrome, cardiovascular events (e.g., QT prolongation), extrapyramidal symptoms, and decreased adherence. Interindividual variability in pharmacogenetics further affects drug efficacy and safety. Innovative approaches like genotype-guided therapy and computerized clinical decision-support systems are promising but not yet widely implemented.

Although polypharmacy may offer symptomatic relief in specific scenarios, it requires careful management due to its potential to cause harm. Rational prescribing, close monitoring, and attention to individual patient factors such as pharmacogenetic profiles are essential to optimize therapy.

Ensuring a balance between therapeutic benefit and adverse effects is crucial when employing polypharmacy in schizophrenia treatment. Integrating personalized medicine strategies, regular monitoring, and deprescribing practices when feasible can enhance clinical outcomes and patient safety.

This review aims to explore the therapeutic potential and safety of herbal bioactive 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.

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.

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.

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.

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.