Expert opinion on drug metabolism & toxicology最新文献

Introduction: Idiosyncratic drug-induced liver injury (iDILI) remains unpredictable. As adverse responses arise in a small fraction of patients, drugs often fail in later drug development stages or post-approval, thereby tremendously increasing costs and putting patients at risk, highlighting the need for accurate early identification of iDILI liabilities.

Covered areas: Using articles from the last 5 years (PubMed), iDILI risk factors are described, in vitro liver models and mechanism-based readout strategies are evaluated on their potential to enable iDILI liability assessment.

Expert opinion: Various in vitro liver models are established for disease modeling and DILI prediction. Drawbacks for each of these seem inevitable, making the evaluation of their application domain and iDILI liability assessment potential crucial. A tiered approach could be considered, whereby compounds are initially screened and flagged using simple fit-for-purpose models for DILI prediction, followed by multicellular liver models that integrate the current knowledge of iDILI onset in combination with mechanistic readouts. Multiplexing models within an integrated mechanism-based testing strategy could improve the safety assessment accuracy. Defined in vitro models should integrate critical hepatocyte intrinsic risk factors as well as adaptive immune system components to refine iDILI liability assessment.

Introduction: The historical context of phytotherapy affects its potential as therapeutic products, and bioactive metabolites are crucial to the pharmacological effects, safety and effectiveness of alternative medicines.

Areas covered: Phytotherapy is of great interest to cancer patients. Therefore, the purpose of this study was to gather publications about the interactions between chemotherapy and phytotherapeutics, medicinal plants, and similar formulations. To find publications published between January 2015 and January 2025, a MEDLINE PubMed search was conducted.

Expert opinion: Several scientists and medical specialists have been looking into the potential of natural items to heal microbial cancer and chemotherapy-related adverse effects. The main factor influencing phytochemicals anticancer effectiveness is their ability to target a variety of pathways, including antimutagenic, antioxidant, and antiproliferative qualities. They can also regulate the host immune response to cancer by improving the surveillance of lymphocytes in cancer cells and lowering the inflammatory milieu. Because carcinogenesis is complex and involves a wide range of factors and signaling cascades, phytochemicals that target several targets may be useful anticancer drugs.

Introduction: Autosomal dominant polycystic kidney disease (ADPKD) is a hereditary condition that leads to a range of systemic manifestations. Many of them require pharmacological interventions. Most patients receive multidrug therapy.

Areas covered: The review summarizes prevalent ADPKD manifestations that might require pharmacological intervention and the most common drug therapies. It lists 2 to 3 prescribed drugs for each manifestation of ADPKD. The review identifies the drug transporters and drug-metabolizing enzymes associated with these drugs, as well as potential drug-drug interactions. To fulfill these aims, a literature search was conducted on PubMed, covering the period from 2021 to July 2024.

Expert opinion: ADPKD therapy often focuses on treating a single manifestation of the disease. However, ADPKD is a complex condition that requires multidrug treatment. While doses of renally eliminated drugs are adjusted in ADPKD patients to account for renal function decline, the condition may change the expression and function of renal and hepatic drug-metabolizing enzymes and transporters, which could result in misevaluations in drug dosing in ADPKD patients and result in under- or overdosing, as well as drug-drug interactions. PBPK modeling offers a valuable tool to predict drug-drug interactions, preventing overdosing, and support precision dosing in patients with ADPKD.

Introduction: Idiosyncratic drug-induced liver injury (iDILI) results in significant patient morbidity and significantly increases the risk of drug development. The current methods to screen for iDILI risk are inadequate.

Areas covered: The general mechanism of iDILI and the current methods to screen for iDILI are reviewed. Then the potential for new biomarkers is explored.

Expert opinion: Better biomarkers of iDILI risk should be based on the mechanism of iDILI. In general, it is an adaptive immune response, specifically CD8⁺ cytotoxic T cells, that is responsible for hepatocyte cell death, not direct toxicity of the drug. Therefore, in vitro cytotoxicity assays represent an artifact not the mechanism of iDILI. Activation of the adaptive immune response leading to iDILI requires an innate immune response, in particular activation of antigen presenting cells. The innate immune response is immediate and unlikely to be idiosyncratic. For example, studies have found that incubation of hepatocytes with drugs causes the release of molecules that activate THP-1-derived macrophages. The response of hepatocytes, the release of damage-associated molecular pattern molecules (DAMPs), especially in extracellular vesicles, and the response of antigen presenting cells (APCs) are likely to provide better biomarkers of iDILI risk.

Introduction: Pharmacological research has traditionally been skewed toward male subjects, leading to uniform treatment guidelines for both men and women that assume similar drug pharmacokinetics across sexes. This oversight contributes to women experiencing adverse drug reactions on average twice as often as men. More recent studies have revealed significant pharmacokinetic differences between the sexes, partly due to different sex hormone levels. Additionally, intraindividual differences in women have been observed due to fluctuating estrogen levels, impacting important aspects of drug pharmacokinetics.

Areas covered: This review highlights key sex differences in drug pharmacokinetics, focusing on absorption, distribution, metabolism, and excretion. A particular emphasis is placed on the role of cytochrome P450 (CYP) and uridine diphosphate-glucuronosyltransferase (UGT) enzymes in drug metabolism, and on the role of P-glycoprotein (P-gp). The impact of estrogens is reviewed by exploring how drug pharmacokinetics change over the menstrual cycle, before and after menopause, and with estrogen-containing medications.

Expert opinion: Personalized dosing based on sex and estrogen levels is important for improving treatment outcomes in female drug users. Clinical trials of drugs likely affected by these factors should incorporate pharmacokinetic studies that distinguish between sexes and evaluate the impact of estrogens, aiming to develop optimized dosing regimens.

Introduction: Endometriosis is a chronic disease characterized by endometriotic cells implanted outside the uterus triggering a chronic inflammatory state. Estradiol stimulates the endometriotic implants, which overexpress estrogen receptor β. Lowering estradiol levels to a range within 40-50 pg/ml allows antagonizing the growth of endometriotic implants and counteracting its-related disabling symptoms.

Areas covered: By blocking the Gonadotropin-Releasing-Hormone (GnRH) receptors, GnRHagonists, peptide GnRHantagonists, non-peptide GnRHantagonists induce hypoestrogenism, due to the suppression of pituitary gonadotropins. This manuscript provides the results of an electronic literature search on pharmacological features of GnRHagonists and GnRHantagonists to treat endometriosis. Hypoestrogenism-dependent side effects can be counteracted by concomitant estrogen and progestin compounds (add-back therapy). GnRHagonists chronic administration induces hypoestrogenism after 10-12 days, since initial administrations stimulate gonadotropin rise (flare-up effect). Peptide GnRHantagonists quickly block GnRH-receptors inducing an immediate hypoestrogenism. Similarly to GnRHagonists, their peptide structure impedes the oral administration. The non-peptide GnRHantagonists have the advantage both of being taken orally and inducing a rapid dose-dependent hypoestrogenism.

Expert opinion: GnRHagonists and peptide GnRHantagonists are effective to treat endometriosis, but require complex ways of administration. Non-peptide GnRHantagonists offer more important prospects in the tailored medical treatment of endometriosis, given their rapid onset of action and their oral way of administration.

Background: Doxorubicin (DOX), a potent antineoplastic drug, can induce cardiotoxicity through its cardiotoxic metabolites catalyzed by CBR 3 and its accumulation in cardiac tissue via the ABCC1 transporter. Here, we investigated CBR3 and ABCC1 genetic polymorphisms affecting doxorubicin cardiotoxicity in breast cancer patients and explored the potential role of brain natriuretic peptide (BNP) as an early cardiac biomarker.

Methods: One hundred Breast cancer patients are receiving DOX treatment. Blood samples were analyzed for CBR3 and ABCC1 gene polymorphisms and echocardiography and BNP biomarkers were used to assess cardiotoxicity at baseline and three months post-DOX treatment.

Results: Following the DOX treatment, CBR3 genotypes showed significant differences in BNP levels and delta BNP (p = 0.001 and 0.014, respectively). There was a significant association between different CBR3 genotypes and BNP levels after DOX (p = 0.001) and delta BNP (p = 0.01), with AA genotypes associated with cardiotoxicity. ABCC1 was not associated significantly with cardiotoxicity (p = 0.67). There was a statistically significant difference between CBR3 genotypes and the occurrence of anemia (p = 0.023).

Conclusion: Detecting CBR3 genetic polymorphisms is crucial for assessing cardiotoxicity before administering DOX, and monitoring BNP levels helps early detection. CBR3 is also associated with DOX anemia.

Background: People with HIV and cancer (PWHC) are often treated with different combinations of antiretroviral and oncology drugs, frequently associated with other co-medications; this significantly increases the risk of potential drug-drug interactions (DDIs).

Research design and methods: A prospective observational study has been carried out from May 2020 to May 2024 to describe the management of therapies in PWHC in an outpatient clinic.

Results: 140 PWHC treated with 42 different antiretroviral and 59 oncology regimens were enrolled, resulting in the identification of 410 DDIs. Of these, 8% were scored as red-flag DDIs). Among antiretroviral medications, 77% of red-flag DDIs involved ritonavir or cobicistat. Paclitaxel was the oncology drug most frequently associated with red-flag-DDIs (77%). Proton pump inhibitors (PPIs) were involved in 19% of red-flag and 32 of orange-flag DDIs. The most frequent recommendations included performing an electrocardiogram (38%), conducting therapeutic drug monitoring (31%), discontinuing PPIs (29%) and/or adjusting the timing of drug intake (28%).

Conclusions: A high prevalence of polypharmacy and clinically relevant DDIs was observed in our cohort of PWHC. A multidisciplinary team could play a pivotal role in optimizing pharmacological therapies in this clinical setting, for example, by reducing the use of PPIs and booster-based antiretroviral regimens.

Introduction: Statins have significantly reduced mortality from cardiovascular diseases by lowering serum cholesterol levels. Beyond their lipid-lowering effects, statins improve vascular function, reduce inflammation, decrease reactive oxygen species (ROS) formation, and stabilize atherosclerotic plaques. However, the mechanisms underlying these pleiotropic effects remain unclear.

Area covered: This narrative review summarizes and discusses epigenetic mechanisms that may explain part of the pleiotropic effects of statins. This approach allows for a reevaluation of statin use beyond its cholesterol-lowering benefits. A structured search was conducted in the PubMed and Scopus databases using specific search terms, including articles published up to August 2024.

Expert opinion: The pleiotropic effects of statins, including those mediated by the isoprenoid pathway, partially explain their clinical benefits. By inhibiting histone deacetylases (HDACs, the 'erasers') and DNA methyltransferases (DNMTs, the 'writers'), statins promote increased histone acetylation and reduced DNA methylation at gene promoter regions. These epigenetic modifications enhance chromatin accessibility, facilitating gene transcription and protecting the cardiovascular system. Further investigation into these epigenetic mechanisms could support the repositioning of statins for broader therapeutic applications. Statins may have benefits extending beyond their role in managing hypercholesterolemia, as their pleiotropic effects contribute to the prevention of cardiovascular disease-related mortality through mechanisms independent of LDL cholesterol reduction.

Background: Drug-induced liver injury (DILI) is an adverse event whose emergence can slow or halt drug development programs. Adaptive immune responses have been implicated for several DILI compounds, and drug-specific T cell responses have been characterized, but there are still many unknowns. We describe the extension of a quantitative systems toxicology (QST) model of DILI to include CD8⁺ T cell-mediated DILI.

Research design and methods: To overcome deficits in quantitative data characterizing CD8⁺ T cell-mediated DILI, a translational strategy leveraged a well-defined mouse ovalbumin (OVA) antigen model and adapted it to represent mouse amodiaquine (AQ)-specific CD8⁺ T cell-mediated DILI, with further adaptations to represent human AQ-specific CD8⁺ T cell-mediated DILI.

Results: DILIsym reproduced published data characterizing mouse OVA-specific CD8⁺ T cell-mediated hepatotoxicity, mouse AQ-specific CD8⁺ T cell-mediated DILI, and human AQ-specific CD8⁺ T cell-mediated DILI. Development identified main drivers of the CD8⁺ T cell response, as well as areas where in vitro assay data could inform the simulation of additional compounds.

Conclusions: The DILIsym CD8⁺ T cell sub-model is well-positioned for systematic testing to improve our understanding of CD8⁺ T cell-mediated DILI. It is not yet predictive but indicates a promising direction to reduce DILI events in drug development.