Expert opinion on drug metabolism & toxicology最新文献

Introduction: Replacement therapy is the global standard of care in hemophilia. However, several unmet needs have favored the development of non-factor therapies. Concizumab, an anti-tissue factor pathway inhibitor (anti-TFPI) administered daily, restores thrombin generation in all hemophilia subtypes.

Areas covered: The pharmacokinetic profile of concizumab from several clinical trials demonstrates target-mediated drug disposition (TMDD) and a consistent exposure-response profile when given daily. Concizumab has an acceptable safe profile and efficacy in hemophilia A or B with and without inhibitors.

Expert opinion: Despite the availability of diverse therapies for hemophilia management, unmet needs remain, including limited prophylaxis for hemophilia B inhibitor patients. Concizumab was developed to address this gap. Its target-mediated drug deposition results in a nonlinear pharmacokinetic profile and a need for a daily injection schedule, which ensures a stable, consistent, and sustained pharmacokinetic profile. While the daily injection may seem demanding, it does not compromise the optimal benefits of concizumab prophylaxis. Moreover, the acceptable safe profile and efficacy of concizumab in bleed prevention in hemophilia A or B with and without inhibitors provide reassurance that it may be a therapeutic option in managing all hemophilia patients.

Introduction: The treatment of schizophrenia and other psychosis-related mental disorders requires long-term therapy with selected drugs possessing adequate pharmacological receptor spectra, relevant to the patient's clinical state. Antipsychotics can interact with cytochrome P450 (CYP) reciprocally affecting each other in different ways. The enzyme plays an important role in the metabolism of antipsychotics, whereas antipsychotics can affect CYP enzymes in the liver and brain.

Areas covered: The effects of short and prolonged administration of antipsychotic drugs belonging to different groups (first-, second- and third-generation) on the expression and activity of CYP enzymes in the liver and brain are presented (based on PubMed 3 December 2024). Possible relations between pharmacological receptor spectra of antipsychotics and their influence on the regulation of cytochrome P450 in the liver and brain are considered. The results are discussed in the light of pharmacological and therapeutic significance.

Expert opinion: During continuous treatment in vivo, the direct mechanisms (drug/metabolite binding to the CYP enzyme) overlap with the effect of antipsychotics on CYP regulation (enzyme induction or inhibition). Clinicians using the information on particular drug-CYP interaction in combination with pharmacogenetic data can make informed decisions about drug selection and dosage, ultimately advancing more effective and safer pharmacotherapy.

Introduction: Inflammatory bowel disease (IBD) treatment remains challenging, with many patients experiencing suboptimal responses despite advances in therapies. This necessitates more precise and personalized approaches.

Areas covered: A literature search was conducted using Embase, Scopus, and PubMed (January 2000-March 2024) with keywords such as 'inflammatory bowel disease,' 'pharmacogenomics,' 'multi-omics,' and 'multi-omics.' This review discusses (1) key pharmacogenomic markers influencing drug metabolism, efficacy, and toxicity; (2) the role of multi-omics (genomics, proteomics, metabolomics) in elucidating IBD pathogenesis and predicting therapeutic outcomes; and (3) emerging technologies such as AI-driven predictive models and organoids. Challenges in translating these tools into clinical practice - including cost, data standardization, and workflow integration - are critically examined.

Expert opinion: Integrating pharmacogenomics with multi-omics holds transformative potential for IBD care. While TPMT genotyping exemplifies current clinical utility, future frameworks will require harmonized multi-omic data to guide therapy selection. Key barriers include high costs of omics profiling, interpretative complexity, and clinician training gaps. Collaborative efforts among researchers, clinicians, and policymakers are essential to validate biomarkers, standardize methodologies, and implement cost-effective assays. Prioritizing real-world studies and AI-powered decision-support tools will accelerate the shift from trial-and-error to personalized IBD management.

Introduction: Aldehyde dehydrogenases (ALDHs) are critical enzymes that protect against cellular damage by metabolizing reactive aldehydes derived from both endogenous processes and environmental exposures. Although cytochrome P450 enzymes dominate metabolic toxicology discussions, the non-P450 ALDH superfamily plays a unique underrecognized role in mitigating the health impacts of the exposome - the totality of lifetime environmental exposures.

Areas covered: This Special Report highlights key insights from recent research on ALDHs, with a focus on their enzymatic diversity, disease-relevant polymorphisms, detoxication functions, and potential as therapeutic targets and clinical biomarkers. A comprehensive review is provided on how ALDHs influence individual susceptibility to environmental stressors, support redox balance, and serve as important mediators in cancer, cardiovascular and neurodegenerative diseases. Clinical implications of ALDH polymorphisms are discussed in the context of precision environmental health. Whereas ALDHs are generally known for their role in detoxifying harmful aldehydes, some ALDHs have been shown to activate other molecules instead. For example, ALDH2 can activate nitroglycerin to nitric oxide-related species - critical for cardioprotective signaling; a process distinct from their typical detoxication function.

Expert opinion: Integrating ALDH biology into exposome research offers a powerful path toward precision risk assessment and possible interventions. Given their public health and clinical relevance, future efforts should prioritize mapping ALDH-exposome interactions, genetic screening, and developing ALDH-targeted interventions.

Introduction: This study aimed to evaluate the detoxification potential of chitosan-functionalized bentonite nanostructures (BT-CTS) against Aflatoxin B1 (AFB1), a hepatotoxic mycotoxin, using both in vitro and in vivo models. The experimental design included synthesis, characterization, and biological evaluation.

Methods: BT-CTS was synthesized through co-sedimentation and characterized using SEM, FTIR, BET, and dynamic light scattering. In vitro cytotoxicity, reactive oxygen species (ROS) generation, and antioxidant status were assessed in HepG2 cells. In vivo, rats were administered AFB1 (12.5 µg/kg/day) with or without BT-CTS (5 g/kg). Oxidative stress markers, serum biochemistry, liver histology, and total antioxidant capacity (TAC) were evaluated.

Results: BT-CTS exhibited a mean particle size of 98 nm and demonstrated a robust porous structure. The IC50 for BT-CTS on HepG2 cells was 5.10 mg/mL. BT-CTS reduced AFB1-induced cytotoxicity and ROS levels in vitro. In vivo, BT-CTS mitigated oxidative stress (lower protein carbonyls and lipid peroxidation), improved TAC, and preserved liver function and histological integrity.

Conclusions: BT-CTS effectively counteracts AFB1-induced toxicity, demonstrating strong potential as a detoxifying agent. However, further studies are needed to confirm its long-term safety and efficacy across various biological systems.

Introduction: Rifamycins are a class of antibiotics crucial for the treatment of tuberculosis (TB). Although the development of rifamycin derivatives has revolutionized TB therapy, they are associated with hepatotoxicity, which limits their clinical use.

Areas covered: This review summarizes the development, clinical applications, and hepatotoxicity of rifamycin derivatives. We highlight the mechanisms of rifamycin drug-induced liver injury (DILI) and discuss strategies to improve the safety profiles of rifamycin derivatives. Relevant literature was reviewed by searching PubMed and SciFinder for articles published up to January 2025.

Expert opinion: The hepatotoxicity of rifamycin derivatives remains a challenge in clinical practice. Further research is needed to clarify the detailed mechanisms of rifamycin-induced liver injury. Mechanism-based strategies are also expected to prevent the toxicity of rifamycin derivatives.

Introduction: The incidence of cancer is constantly increasing, and current cytostatics are not effective enough and cause serious side effects. Thio/semicarbazide derivatives seem to be promising candidates for anticancer drugs. This systematic review aimed to analyze comparatively the ADMET profiles of thiosemicarbazides and semicarbazides with proven antitumor activity published through August 2024.

Methods: A search of PubMed, ScienceDirect and Google Scholar databases was performed. Qualified compounds were subjected to in silico analysis using ADMETlab 2.0 software. The data were statistically analyzed (Student's t-test, Mann-Whitney U test, Chi²).

Results: Comparative analysis showed that semicarbazides have more favorable intestinal absorption properties and lower biological activity but have higher selectivity of action and lower risk of drug interactions. Thiosemicarbazides have a higher probability of metabolic activity with concomitant increased toxicity. These compounds show significantly higher levels of binding to plasma proteins, a lower average percentage of the unbound fraction, and a longer half-life.

Conclusions: In light of anticancer therapies, thiosemicarbazides can cause increased oxidative stress and DNA damage, which is one strategy for cancer treatment. However, semicarbazides are better candidates for anticancer drug trials because of their better pharmacokinetic and pharmacodynamic profiles and lower toxicity.

Background: Cephalosporins are the second most prescribed antibiotics worldwide and are applied for a wide range of infective indications. However, there is limited information about the toxicity profile of cephalosporins in pediatrics. Consequently, the aim of this narrative review is to provide a complete overview of the toxicity associated with cephalosporin treatment in children.

Areas covered: Adverse events (AEs) and toxicity of cephalosporin antibiotics in pediatrics are reviewed.

Expert opinion/commentary: Overall, 35 studies concerning AEs in cephalosporins were identified. Most AEs were reported in the system organ classes (SOC) gastrointestinal (GI), infections and infestations, and skin and subcutaneous. For oral administration, the most common AE of the GI SOC were diarrhea with an incidence rate varying between from 0.6% to 15.2%, for which cefdinir was the most reported cephalosporin with AE. Observed incidence rates for a diverse spectrum of SOC and AEs varied widely due to heterogeneity in study populations and lack of AE reporting criteria. This narrative review provides a complete overview of reported AEs in literature caused by cephalosporins in pediatrics. In the future, cephalosporin therapeutic drug monitoring might provide insights into toxicity threshold concentrations.

Introduction: Mitragyna speciosa (Korth.) Havil. (Rubiaceae), commonly known as kratom, is a tropical tree native to Southeast Asia, traditionally used for its diverse ethnopharmacological activities, including analgesic and anxiolytic effects. Kratom's unique pharmacological profile allows it to function as a stimulant at low doses and produces opioid-like effects at high doses, making it a potential alternative for pain management and mitigation of opioid use disorder.

Areas covered: Google Scholar and PubMed, along with FAERS database, were systematically searched to evaluate the clinical applications of kratom by examining its drug interactions, which can significantly impact the pharmacokinetics and pharmacodynamics of concomitant medications. By examining current evidence, this review aims to highlight the importance of establishing safe clinical practices and protocols for healthcare providers and patients.

Expert opinion: Evaluating drug interactions in kratom usage is clinically imperative because kratom's bioactive alkaloids can interact with the pharmacokinetic and pharmacodynamic processes of concurrent medications, potentially resulting in adverse effects or compromised therapeutic outcomes. This review presents an expert opinion on the clinical relevance of kratom's interactions with drugs, aiming to inform clinical practice, highlight ethical and regulatory considerations, and propose future research directions to improve the understanding of kratom's pharmacological profile and enhance user safety.

Background: Tegoprazan (LXI-15028), a novel potassium-competitive acid blocker, has shown great efficacy in treating acid-related disorders. However, its metabolic and excretion characteristics are not fully understood.

Research design and methods: A single oral dose of 50 mg/150 μCi [¹⁴C]tegoprazan was administered to six healthy subjects. Blood, urine and fecal samples were collected and measured for total radioactivity (TRA), tegoprazan and metabolites. Its safety was also assessed.

Results: The maximum concentrations (C_max) of tegoprazan and TRA in plasma were 634 ng/mL and 990 ng eq./mL, respectively, at 0.5 h post dose. Tegoprazan and its N-demethylation metabolite (M1) were the major drug-related compounds in plasma, accounting for 34.84% and 40.10% of TRA, respectively. The half-life (t_1/2) of TRA (8.72 h) was longer than that of tegoprazan (4.33 h) in plasma, indicating slower metabolite elimination. Tegoprazan was excreted through both the urine (50.51 ± 3.35%) and feces (47.26 ± 3.06%). The main metabolic pathways of tegoprazan are demethylation, oxidation, glucuronidation and sulfation. There were no serious adverse events observed in this study.

Conclusions: Tegoprazan is widely metabolized and excreted completely in humans. Tegoprazan and M1 were the primary compounds present in the circulation.

Clinical trial registration: www.clinicaltrials.gov identifier is NCT05883306.