Current drug metabolism最新文献

Introduction: Drug interactions necessitate careful consideration in clinical practice. It is imperative for clinicians and pharmacists to monitor drug exposure and the co-administration of medications promptly in order to avert adverse outcomes and achieve optimal efficacy.

Objectives: The prevalence of oral lesions varies from 28% to 60% in the short term after renal transplantation. The clinical use of metronidazole in the treatment of anaerobic bacterial infections among solid organ transplant recipients has been complicated by the potentially significant and unpredictable drug-drug interactions.

Methods: We present an unexpected clinically significant drug-drug interaction between tacrolimus and metronidazole in the early period after renal transplantation and describe the potential mechanism and clinical characteristics of this drug-drug interaction through a literature review.

Results: A 34-year-old female experienced a 65% increase in dose-normalized tacrolimus trough concentration after intravenous administration of metronidazole at 1000 mg/day for 8 days. When metronidazole was switched from intravenous to oral for 5 days, dose-normalized tacrolimus trough concentration was still increased by 52.4%. The magnitude of tacrolimus-metronidazole drug-drug interaction seems to be contingent upon the dose of metronidazole and the route of metronidazole administration. After cessation of metronidazole for one month, this drug-drug interaction, as assessed by weight-normalized tacrolimus dose, may still persist.

Conclusion: In the early period following renal transplantation, the long-term concomitant use of metronidazole is likely to elevate the trough concentration of tacrolimus. Gene screening for CYP3A5*3/*3 and ABCB1 3435C>T in recipients of solid organ transplants may support individualized tacrolimus prescribing and facilitate the mitigation of risks associated with drug-drug interactions.

Nanocochleates are novel lipid-based nanoparticles with a distinctive, multilayered, rolledup structure that resembles the spirals of a cochlea. They form when bivalent cations, such as calcium, interact with negatively charged lipid bilayers. These structures are gaining popularity in drug delivery due to their stability, biocompatibility, and ability to encapsulate and shield a wide range of bioactive substances, including hydrophobic drugs, peptides, and nucleic acids. Nanocochelates can withstand harsh environmental conditions, such as acidic pH or enzymatic degradation, making them suitable carriers for oral, injectable, and transdermal medication administration. Their unique construction enables the gradual release of encapsulated medicines, thereby increasing bioavailability and therapeutic effectiveness. Additionally, nanocochleates can target specific tissues or cells, allowing for precision medical methods. A recent study demonstrates their promise for overcoming issues in the administration of poorly watersoluble medicines, gene therapy agents, and vaccines. Nanocochleates have shown promise in preclinical trials for the management of inflammatory diseases, cancer, and infectious diseases. Despite their potential, further research is needed to optimize large-scale manufacturing, maintain uniform quality, and address regulatory challenges. This review provides a detailed discussion of nanocochleate preparation methods, with a particular focus on entrapment, hydrogel approaches, and dialysis methods. The paper reviews characterization experiments, including particle size measurements, encapsulation effectiveness, surface morphology, and in vitro release tests. Furthermore, the article discusses the feasibility of industrial-scale formation with pure lipid feedstock.

Alzheimer's disease (AD), the most common form of dementia, is characterized by progressive cognitive decline and neuropathological hallmarks, including amyloid-beta plaques and tau tangles. Emerging evidence implicates metabolic dysfunction as a critical contributor to the pathogenesis and progression of AD. Impaired glucose metabolism, mitochondrial dysfunction, oxidative stress, and lipid dysregulation are frequently observed in AD brains, suggesting that metabolic dysfunction may exacerbate neurodegeneration and cognitive deficits. This review explores the therapeutic potential of targeting metabolic pathways to mitigate AD pathology. Key metabolic disruptions, including insulin resistance, reduced cerebral glucose utilization, and mitochondrial inefficiency, are closely linked to neuronal energy deficits and synaptic dysfunction. Therapeutic approaches, such as insulin sensitizers, ketogenic diets, and mitochondrial-targeted antioxidants, have shown promise in preclinical and early clinical studies. Additionally, strategies to modulate lipid metabolism, such as enhancing cholesterol efflux via APOE or reducing neurotoxic ceramides, offer potential avenues for intervention. The review also highlights the roles of neuroinflammation and oxidative stress as mediators of metabolic dysfunction in AD, underscoring the need for multifaceted approaches that target both metabolic and inflammatory pathways. The emerging field of precision medicine offers opportunities to tailor interventions based on individual metabolic profiles, potentially enhancing treatment efficacy. Despite the growing recognition of metabolic dysfunction in AD, translating these insights into effective therapies remains challenging due to the disease's complexity and heterogeneity. Future research must focus on elucidating the interplay between metabolic pathways and AD pathology, identifying reliable biomarkers, and designing targeted interventions. By addressing the metabolic underpinnings of AD, this review underscores the potential of metabolic reprogramming as a novel and integrative therapeutic strategy to slow or prevent disease progression and improve patient outcomes.

Introduction: Remimazolam is a short-acting sedative/anesthetic. For safe breastfeeding, information on the extent and possible risks of remimazolam being passed over to the infant through mother´s milk is needed. The objective of this work was to study the transfer of remimazolam from maternal to infant circulation by mother´s milk in an animal model.

Methods: Three lactating British milk sheep received intravenous remimazolam (0.4 mg/kg bolus plus 4-hrinfusion at 1 or 2 mg/kg/hour). Drug profiles were recorded in plasma and milk. Six suckling lambs were administered remimazolam by intravenous and oral gavage administration for a comparison of plasma concentration profiles of remimazolam and its primary metabolite, CNS7054.

Results: Treatment of lactating sheep induced dose-dependent sedation and loss of consciousness. At the end of infusion, the concentration of remimazolam was higher in milk than in plasma. The subsequent elimination of remimazolam from milk was rapid, although somewhat slower than from plasma.

Discussion: In lambs, intravenous, but not oral, remimazolam (2 mg) caused different grades of sedation/anesthesia (fully reversible within 8 to 15 min). Mean plasma C_max was 278.3 ng/mL after intravenous and 1.3 ng/mL after oral administration. Oral gavage resulted in a sizable plasma concentration of CNS7054 (Cmax around 100 ng/mL), indicating efficient intestinal absorption of the parent drug, followed by extensive firstpass metabolic elimination, leading to negligible bioavailability of oral remimazolam.

Conclusion: In mother´s milk, remimazolam reaches higher concentrations than in plasma and is cleared by redistribution to the central compartment for final hepatic elimination. In lambs, oral remimazolam results in minimal plasma concentrations, suggesting that safety concerns regarding breast-fed infants would be minor and could be completely alleviated by a short nursing interruption.

Introduction: Shenlian formula (SL) has been widely used to treat various diseases, including type 2 diabetes mellitus and atherosclerosis (AS). Pathological states can significantly alter drug pharmacokinetics (PK) compared to normal physiology, primarily by modulating biological membrane permeability and metabolic enzyme activity, thereby affecting drug absorption, distribution, metabolism, and excretion. However, the specific influence of AS on the PK profile of SL remains uncharacterized.

Objective: To investigate the plasma PK of five components (Salvianolic acid A (SAA), Danshensu (DSS), Andrographolide (AND), Neoandrographolide (NAND), and Dehydrated andrographolide (DDAND),) which were the ingredients of SL, in physiological and AS rats administered SL intragastrically.

Methods: The AS SD rat model was induced with a high-fat diet, carotid balloon injury, and VD3 injections. A validated LC-MS/MS method quantified plasma concentrations to assess PK parameters.

Results and discussion: The validation parameters were all in accordance with the current standards. Comparative PK analysis revealed significant intergroup disparities between the AS and normal groups. The value of C_max and AUC_0-t for DSS was significantly decreased (P<0.05) in the AS group, which indicated that the absorptive amount in vivo was remarkably attenuated in the pathological state. Additionally, the variation trend of AND under C_max and AUC_0-t values were consistent with the alteration trend of DSS. Furthermore, the T_max of NAND in the AS group was significantly reduced (P<0.05), confirming that the pathological state accelerated the absorption rate of NAND, thereby shortening the time required for NAND to reach its maximum concentration in the body.

Conclusion: We established and validated a sensitive LC-MS/MS method for the simultaneous quantification of five bioactive components of SL in rat plasma. This method is applicable to both physiological and pathological states. Comparative pharmacokinetic analysis revealed significant differences in the systemic exposure of all five analytes between AS and normal rats. These findings provide critical PK evidence for optimizing SL dosage regimens in AS patients, underscoring the imperative to consider the disease' status when determining therapeutic strategies for traditional Chinese medicine formulations.

Introduction: Hepatic lipid accumulation (steatosis) is an early indicator of non-alcoholic fatty liver disease (NAFLD), preceding fibrosis and cirrhosis. Understanding its effects on drug-metabolizing enzymes (DMEs) and transporters is crucial for assessing potential alterations in drug disposition among NAFLD patients. This study aimed to replicate steatosis in an in vitro HepaRG cell model and analyze its impact on DMEs and transporters.

Methods: Differentiated HepaRG cells were treated with a mixture of saturated (palmitate) and unsaturated (oleate) fatty acids (in a 1:2 ratio at 0.5 mM), complexed with BSA for 72 hours to induce lipid accumulation. Confirmation of steatosis was performed using Oil Red O staining and triglyceride (TG) quantification, while cell viability was assessed via the WST-1 assay. RNA sequencing and SWATHMS proteomic analysis were employed to identify differentially expressed transcripts and proteins in lipid-loaded cells compared to controls.

Results: Lipid loading resulted in a ~6-fold increase in TG concentration without compromising cell viability. Transcriptomic analysis identified 393 differentially expressed transcripts (89 upregulated, 304 downregulated), while proteomic analysis detected 165 differentially expressed proteins (127 upregulated, 38 downregulated). Notably, key mRNA transcripts related to transcription factors (NR1I2, HNF4α), phase 1 DMEs (CYP1A2, 2B6, 2C8, 2C9, 2C19, 3A4), phase 2 DMEs (UGT1A6, 2B7, SULT2A1, 1E1), and transporters (ABCC11, ABCG5, SLCO2B1, SLC10A1) exhibited significant downregulation.

Discussion: The observed alterations in DMEs and transporters suggest a potential shift in drug metabolism pathways under NAFLD conditions. Downregulation of transcription factors and metabolic enzymes could impact drug efficacy and toxicity, necessitating further research into the pharmacokinetic implications.

Conclusion: The in vitro hepatic steatosis model demonstrated significant changes in the expression of clinically relevant DMEs and transporters. These findings highlight the importance of considering NAFLD-induced metabolic alterations when assessing drug disposition in affected patients.

Background: Cnidii Fructus (CF) is a herbal medicine with pharmacological activities such as antitumor, antiviral, antiallergic, antipruritic effects, and so on.

Objective: In this study, an ultra-high performance liquid chromatography/tandem mass spectrometry (UPLC- MS/MS) method was prepared and verified to measure the concentrations of seven analytes (bergapten, xanthotoxol, xanthotoxin, imperatorin, osthole, isopimpinellin, isoimperatorin) in HepG2 cells.

Methods: The separation of seven analytes was performed on an ACQUITY UPLC® BEH C18 column (2.1×100 mm, 1.7 μm) with a gradient mobile phase system of 0.1% formic acid/water and acetonitrile.

Results: The CV of analytes was within 7.77%, and the bias was in the range of -5.43%-3.84%. The matrix effects of analytes ranged from 92.95% to 104.58%, and the extraction recoveries ranged from 76.45% to 104.69%. The relative standard deviation of stability results was less than 8.21%, indicating that seven analytes were stable.

Conclusion: The method was successfully applied to the determination of the content of seven analytes of CF extracts by UPLC-MS/MS, and the results will provide a reference for the cellular pharmacokinetics of CF.

Objective: Tacrolimus, a calcineurin inhibitor (CNI), is the first-line treatment for chronic myeloid leukemia (CML) and advanced gastrointestinal stromal tumors (GIST). Imatinib and tacrolimus are both substrates of the hepatic enzymes CYP3A4/5 and efflux transporter P-gp, so drug-drug interactions may occur during their co-administration treatment. Therefore, this study aimed to evaluate the pharmacokinetic interaction between imatinib and tacrolimus in rats.

Methods: Rats were divided into groups I (30 mg/kg imatinib administered for 14 days), II (1.89 mg/kg tacrolimus and 30 mg/kg imatinib administered for 14 days), III (30mg/kg imatinib and 0.63mg/kg tacrolimus administered for 14 days), IV (1.89mg/kg tacrolimus for 14 days), and V (10mg/kg imatinib and 1.89mg/kg tacrolimus for 14 days). Blood samples were determined for whole blood of tacrolimus, plasma of imatinib, and Ndesmethyl imatinib concentrations using ultra-performance liquid chromatography-mass spectrometry.

Results: After 1 day of a single dose, tacrolimus had no significant effect on the pharmacokinetics of imatinib and N-desmethyl imatinib; imatinib significantly increased the AUC and C_max of tacrolimus (P < 0.05). After 14 days of multiple doses, tacrolimus significantly reduced the AUC and C_max of imatinib and N-desmethyl imatinib (P < 0.05). Further, imatinib significantly increased AUC_0-24 and AUC_0-∞ of tacrolimus (P < 0.05).

Conclusion: Imatinib increased tacrolimus blood concentrations after single and multiple administrations. Tacrolimus did not significantly affect the pharmacokinetics of imatinib after a single dose; however, tacrolimus might impact the absorption and metabolism of imatinib after multiple doses. The results showed that when imatinib and tacrolimus were co-administered, attention should be paid to the presence of drug-drug interactions.

Attention Deficit Hyperactivity Disorder (ADHD) is a prevalent neurodevelopmental disorder characterized by symptoms of hyperactivity, inattention, and impulsivity, significantly impacting individuals' daily functioning and quality of life. This manuscript explores the intricate relationship between the gut microbiome and ADHD, emphasizing the role of the gut-brain axis, a bidirectional communication pathway linking the central nervous system (CNS) and the gastrointestinal tract (GIT). The composition of gut microbiota influences several physiological processes, including immune function, metabolism, and the production of neuroactive metabolites, which are critical for cognitive functions such as memory and decision-making. The review discusses alternative therapeutic options, including dietary modifications, synbiotics, and specific diets like the ketogenic diet, which may offer promising outcomes in managing ADHD symptoms. Further research is necessary to establish the efficacy and mechanisms of action of synbiotics and dietary interventions, despite preliminary studies suggesting their potential benefits. This review article aims to provide a comprehensive overview of the current understanding of the gut microbiome's impact on ADHD, highlighting the need for continued investigation into innovative treatment strategies that leverage the gut-brain connection.