Current drug metabolism最新文献

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.

Background: Tetrandrine (TET) demonstrates therapeutic potential for hypoxic pulmonary hypertension (HPH); however, its precise pharmacological mechanisms remain unclear. In this study, we aimed to investigate the effects of TET on pulmonary vascular remodeling (PVR) in HPH and elucidate the molecular pathways through which TET ameliorates HPH.

Methods: We established a rat model of HPH and evaluated the therapeutic effects of TET by measuring hemodynamic parameters, assessing right ventricular hypertrophy, and analyzing pathological changes in lung tissue. To explore the molecular mechanisms, we carried out comprehensive analyses using transcriptome and untargeted metabolomics technologies to examine the impact of TET on gene expression and metabolite profiles in the lung tissue of HPH rats. Using data from these multiomics analyses, we performed biochemical assays, immunofluorescence staining, and Western blotting to validate the effects of TET on vasoconstriction and angiogenesis-related factors. These experiments provide further evidence of the anti-HPH and anti-PVR properties of TET.

Results: TET intervention significantly reduced hemodynamic parameters, including mean pulmonary arterial pressure (mPAP) and right ventricular systolic pressure (RVSP), as well as right ventricular hypertrophy indices, such as the right ventricular hypertrophy index (RVHI) and right ventricle-to-body weight ratio (RV/BW), in HPH rats. TET inhibited smooth muscle cell proliferation and alleviated pathological changes in lung tissue. Transcriptome and metabolome analyses revealed that genes affected by TET intervention were enriched in pathways related to PVR, including those involved in endothelial and smooth muscle cell proliferation, angiogenesis, and blood vessel morphogenesis. Metabolites were predominantly associated with the arachidonic acid (AA) metabolism pathway. Differentially expressed genes included Cyp4a1, Cyp4a3, Cyp2u1, and Alox15. Validation experiments demonstrated that TET upregulated ALOX15 protein expression and downregulated CYP4A and CYP2U1 proteins, modulating levels of arachidonate metabolites 20-HETE and 15(S)-HPETE. We further observed that TET reduced the levels of PVR markers, including endothelin-1 (ET-1) secretion, while increasing nitric oxide (NO) release. TET also decreased the expression of cell proliferation markers PCNA and Ki-67 and elevated the endothelial marker CD31. Moreover, TET intervention suppressed angiogenic and vasoconstrictive factors, such as MMP-9, TGF-β1, IGF2, and PDGF-B, while enhancing levels of FGF9 and NOS3.

Conclusion: Our findings highlight the protective effects of TET on lung tissue in HPH mediated through the regulation of 15(S)-HPETE and 20-HETE within the arachidonic acid metabolism pathway. This regulation inhibits pulmonary angiogenesis and vasoconstriction, ultimately improving PVR in HPH.

Background: The use of computer-aided toxicity and Pharmacokinetic (PK) prediction studies are of significant interest to pharmaceutical industries as a complementary approach to traditional experimental methods in predicting potential drug candidates.

Methods: In the present study, in-silico pharmacokinetic properties (ADME), drug-likeness, and toxicity profiles of valeric acid were examined using SwissADME and ADMETlab web tools.

Results: The drug-likeness prediction results revealed that valeric acid adheres to the Lipinski rule, Pfizer rule, and GlaxoSmithKline (GSK) rule. From a pharmacokinetic perspective, valeric acid is anticipated to have the best absorption profile including cell permeability and bioavailability. Plasma Protein Binding (PPB) and Blood-Brain Barrier (BBB) permeability may have a positive effect on Central Nervous System modulating (CNS). There is a minimal chance of it being a substrate for cytochrome P2D6 (CYP). Except for a "very slight risk" for eye corrosion and eye irritation, none of the well-known toxicities in valeric acid were anticipated, which was compatible with wet-lab data. The molecule possesses no environmental hazard as analyzed with common indicators such as bio-concentration factor and LC₅₀ for fathead minnow and daphnia magna. The toxicity parameters identified valeric acid as nontoxic to androgen receptors, antioxidant response element, mitochondrial membrane receptor, heat shock element, and tumor suppressor protein (p53), except Peroxisome Proliferator-Activated Receptor- gamma (PPAR-γ) was found to be medium toxicity. However, no toxicophores were found out of seven parameters.

Conclusion: Overall, the ADMETLab evaluated that valeric acid has favorable pharmacokinetic and drug-likeness profiles, making it a promising drug candidate for new drug development.