Expert opinion on drug metabolism & toxicology最新文献

Introduction: Combined oral contraceptives (COCs), commonly referred to as the 'pill,' are a reliable form of contraception used by a vast majority of women of reproductive potential. COCs contain two primary components: estrogens and progestins. In addition to protection against pregnancy, COCs also confer several significant non-contraceptive benefits, such as the treatment of polycystic ovary syndrome. Given that polypharmacy is a common practice, drug interactions between COCs and concomitant therapies can adversely impact efficacy and safety.

Areas covered: This article systematically reviews literature published up to December 2025, from PubMed and Scopus on drug-metabolizing enzymes and transporters in the disposition of key COC components, drug-COC interactions (DCIs), and clinically relevant safety concerns.

Expert opinion: Progestins are primarily metabolized through phase I enzymes, especially CYP3A4, whereas estrogen metabolism relies on a combination of both phase I and phase II pathways. Nevertheless, the contribution of phase II enzymes to the clearance of COCs remains underappreciated. Much of the existing studies have focused on characterizing metabolic pathways and pharmacokinetic effects rather than assessing meaningful clinical outcomes. While pharmacokinetic interactions can theoretically predict potential adverse effects, robust DCI studies that incorporate real-world clinical outcomes are still critically needed.

Introduction: Letermovir is an antiviral licensed for the prophylaxis of cytomegalovirus (CMV) infection in CMV seropositive allogeneic hematopoietic stem cell transplant (HSCT) recipients. Unlike other anti-CMV agents, letermovir has a favorable toxicity profile. Although the efficacy of letermovir in preventing CMV infection has been demonstrated in clinical trials, virologic failure may occur possibly due to suboptimal letermovir concentrations.

Areas covered: This review summarizes the pharmacology of letermovir with emphasis on factors that can impact letermovir exposure including drug-drug interactions in a population frequently on multiple medications. Studies on letermovir exposure-response relationship are summarized, and the role of therapeutic drug monitoring (TDM) is discussed. A PubMed search using the terms: 'letermovir' and the following terms 'pharmacodynamics,' 'resistances,' 'pharmacokinetics,' 'drug-drug interactions, 'therapeutic drug monitoring' were used to compile data until November 2025.

Expert opinion: Letermovir meets several criteria for TDM, including large interindividual pharmacokinetic variability and exposure-response relationship, albeit, the latter has not been consistently demonstrated. Randomized controlled trials are needed to determine the clinical benefit of letermovir TDM in HSCT recipients. Furthermore, studies are warranted to characterize letermovir pharmacokinetics in situations encountered in clinical practice (complex drug-drug interactions and/or organ dysfunction) and to determine letermovir optimal dosing in the pediatric population.

Introduction: Methotrexate (MTX) is a type of disease-modifying antirheumatic drug and one of the most effective anticancer agents in clinical practices. However, hepatotoxicity and nephrotoxicity are common side effects associated with MTX therapy. Complementary natural medicines for treating hepatorenal toxicity have received widespread research interest.

Area covered: Plant-based natural products have shown promise in managing organ toxicities caused by various drugs. These natural products possess medicinal properties that can be used as a complementary therapy to counteract MTX-induced hepatotoxicity and nephrotoxicity. This study comprehensively reviewed the research on natural products like berberine, gallic acid, resveratrol, etc. that show potential in moderating MTX-induced hepatotoxicity and nephrotoxicity in preclinical models. We explored Google Scholar, Scopus, and PubMed for studies on plant-based natural products and their protective actions against MTX-induced hepatotoxicity and nephrotoxicity. This updated report can be very valuable in deveoping phytotherapeutics for effectively managing the toxicities associated with MTX therapy.

Expert opinion: The studied evidence underscores the promising potential of phytochemicals in mitigating MTX-induced hepatotoxicity and nephrotoxicity via different mechanisms. Given the extensive usage of MTX in various diseases, additional clinical studies are critical to further authenticate these results and optimize phytotherapeutic approaches for enhancing the safety and efficacy of treatment.

Introduction: Drug clearance is a fundamental pharmacokinetic parameter that governs drug elimination and influences half-life, bioavailability, and dose selection. Clearance occurs through multiple pathways, including hepatic metabolism, renal elimination, and biliary excretion. This process is primarily mediated by drug-metabolizing enzymes and drug transporters. Optimizing clearance requires a clear understanding of the dominant elimination pathways and strategic use of in vitro and in vivo tools to inform structure-clearance relationships.

Areas covered: This article discusses in vitro and in vivo methods for characterizing clearance and presents perspectives on their application with case studies. In vitro systems such as liver microsomes and hepatocytes offer early insights into metabolic stability and transporter involvement. In vivo models combined with physiologically based pharmacokinetic modeling, deliver mechanistic understanding of drug disposition processes. The article aims to equip early-career scientists with the knowledge and tools to conduct robust drug clearance assessments.

Expert opinion: A comprehensive understanding of drug clearance mechanisms is essential for optimizing pharmacokinetics and guiding development strategies. Integrating diverse experimental and modeling approaches will be critical for advancing ADME science and improving translational success. This article provides a practical framework for characterizing and translating drug clearance, integrating both in vitro and in vivo approaches.

Introduction: Pregnant women are customarily excluded from phase 1 and 2 clinical trials which, provide the earliest indication of drug safety and efficacy. This leads to lack of pregnancy-specific safety information for over 90% of approved drugs, including many commonly used during the first trimester.

Areas covered: In this review, we highlight the importance of pregnancy-induced changes in pharmacokinetics, commonly used indices of fetal exposure to maternal drugs, and their limitations. Inter-species differences make data from animal models used in preclinical embryofetal development toxicity studies poorly translatable to humans. Real-world evidence may bridge some of this gap, but it is mostly retrospective in nature and available postmarketing. We reviewed emerging human relevant models that are showing promise in studying aspects of human pregnancy, highlighting opportunities for further advances.

Expert opinion: While pregnancy exposure data may help in understanding how pregnancy might influence therapeutic outcomes, fetal drug exposure is not a metric of safety. Adequately addressing questions about drug safety during pregnancy will necessarily include a battery of assays based on human relevant models, each sufficiently validated for an aspect of Developmental and Reproductive Toxicology (DART) as its use case.

Background: Anthracyclines (ANTs) remain essential in many anticancer regimens, yet their clinical utility is often limited by multidrug resistance. Recent studies suggest that Bruton's tyrosine kinase inhibitors (BTKis) may enhance the efficacy of ANT-based therapies, including those targeting brain tumors. This study investigates how tirabrutinib may contribute to such enhancement via interactions with aldo-keto reductase 1C3 (AKR1C3) and ABC efflux transporters.

Research design and methods: The inhibitory potential of tirabrutinib was evaluated using recombinant enzymes, transiently transfected HCT116 cells, and cell lines with differential AKR1C3 expression (T98G, MRC-5). ABC transporter-expressing cells were used to assess daunorubicin accumulation. Western blotting was used to examine whether tirabrutinib alters AKR1C3 protein expression.

Results: Tirabrutinib inhibited daunorubicin metabolism in both recombinant AKR1C3 assays and AKR1C3-expressing cells, but had no effect in non-expressing cells. It also enhanced intracellular accumulation of daunorubicin in relevant models. No significant changes in AKR1C3 expression were observed following tirabrutinib treatment.

Conclusions: Our in vitro data demonstrate that tirabrutinib influences daunorubicin pharmacodynamics by targeting both metabolic and transport pathways. However, Chou-Talalay analysis highlights the importance of appropriate dosing to achieve therapeutic synergy in combination regimens.

Introduction: The prescription of psychotropic drugs during pregnancy is a constantly increasing practice, but its safety information remains limited. On the other side, while concerns about teratogenicity persist, it is also evident that mothers' psychiatric disorders represent a risk factor for both them and the infants and cannot be neglected or left untreated. Therefore, careful monitoring and dose adjustments are essential to minimize risks while ensuring treatment efficacy.

Areas covered: The present article is a narrative review of the literature on psychotropic drug use in pregnancy and lactation, attempting to summarize their benefits and risks while considering maternal and fetal outcomes.

Expert opinion: Whenever possible, medications should be avoided in the first trimester, with the lowest effective dose used throughout pregnancy. In severe cases, drugs cannot be stopped as discontinuation can lead to relapse, but they require individualized risk-benefit assessments. For lactating mothers, drugs with established safety profiles should be prioritized. Further research is needed to clarify long-term effects and support evidence-based decisions in maternal mental health care.

Background: Betahistine hydrochloride is critical for Ménière's syndrome treatment. Validating bioequivalence of generic and reference formulations under fasting/postprandial conditions is key for clinical substitution.

Research design and methods: Single-center, randomized, open-label, two-period crossover study; 26 healthy subjects per arm. Test (Tianfang) and reference (Mylan) 8 mg tablets were compared. Plasma 2-pyridineacetic acid quantified via UPLC-MS/MS. Safety monitored via adverse events, vital signs, and labs.

Results: 90% CIs for Cmax/AUC0-t/AUC0-∞ (test/reference) were 80%-125%. Adverse events were mild (fasting: test 23.1%, reference 19.2%; postprandial: test 26.9%, reference 7.7%); no severe reactions.

Conclusions: Test formulation is bioequivalent and well-tolerated to reference, supporting interchangeability. Limitations: small single-center sample, healthy subjects.