Expert opinion on drug metabolism & toxicology最新文献

Introduction: Medication use is highly prevalent in breastfeeding persons, posing potential risks for drug exposure to nursing infants. Transporters in the lactating mammary gland carry pharmacological and toxicological significance, as they can mediate the active transfer of drugs and nutrients into breastmilk.

Areas covered: In this narrative review, we searched and compiled current knowledge on the transport of drugs in the human mammary gland from literature indexed in PubMed (current as of 25 October 2024), and clinical evidence demonstrating active transport of drugs into milk is provided. In vitro and in vivo models of the mammary gland are outlined in brief and known drug transporters at the blood-milk barrier and their potential relevance to drug concentrations in milk are described in detail.

Expert opinion: Although clinical data show that membrane transporters mediate the transfer of multiple drugs into breast milk, our ability to predict milk concentrations for these drugs is limited. Improving our understanding of the transporter biology and pharmacology in the mammary gland is crucial for developing models to predict drug concentrations in human milk, which will support clinicians and lactating individuals in making rational decisions to balance the benefits of breastfeeding and the risks of drug exposure to infants.

Introduction: Alopecia, encompassing non-scarring and scarring types, presents therapeutic challenges requiring individualized approaches based on pathophysiology and treatment responses. A comprehensive literature search of PubMed/MEDLINE, Embase, Cochrane Library, Scopus, and Web of Science (2015-2024) focused on randomized controlled trials, meta-analyses, and observational studies.

Areas covered: This review evaluates pharmacological strategies for androgenetic alopecia (AGA), alopecia areata (AA), and scarring alopecias, emphasizing efficacy and safety. Treatments for non-scarring alopecia include finasteride, minoxidil, JAK inhibitors, and antiandrogens like spironolactone. JAK inhibitors, such as baricitinib, show promise for AA but require monitoring due to immune suppression risks. Scarring alopecias, including lichen planopilaris and discoid lupus erythematosus, are managed with systemic agents like hydroxychloroquine and corticosteroids, alongside adjunctive topical and laser therapies.

Expert opinion: The future of alopecia treatment is poised for transformation, particularly for AA and AGA. Emerging targeted therapies, such as JAK inhibitors for AA, represent significant advancements. Additionally, innovations in regenerative medicine and delivery systems for AGA treatments, alongside nanotechnology and 3D bioprinting, promise enhanced efficacy and personalization. This shift toward mechanism-targeted and individualized therapy is expected to improve outcomes for various alopecia subtypes.

Introduction: Drug-induced liver injury (DILI) is a leading cause of acute liver failure. Hepatotoxicity typically occurs only in a subset of individuals after prolonged exposure and constitutes a major risk factor for the termination of drug development projects.

Areas covered: We provide an overview of available human liver models for DILI research and discuss how they have been used to aid in early risk assessments and to mitigate the risk of project closures due to DILI in clinical stages. We summarize the different data that can be provided by such models and illustrate how these diverse data types can be interfaced with machine learning strategies to improve predictions of liver safety liabilities.

Expert opinion: Advanced human liver models closely mimic human liver phenotypes and functions for many weeks, allowing for the recapitulation of hepatotoxicity events in vitro. Integration of the biochemical, histological, and toxicogenomic output data from these models with physicochemical compound properties using different machine learning architectures holds promise to enhance preclinical DILI predictions. However, to realize this aim, it is important to benchmark the available liver models on test sets of DILI positive and negative compounds and to carefully annotate and share the resulting data.

Introduction: Ertugliflozin is the fourth sodium-glucose co-transporter (SGLT2) inhibitor approved by the US FDA in 2017 for the treatment of type 2 diabetes mellitus.

Areas covered: The main purpose of this review is to evaluate the clinical efficacy and safety of ertugliflozin. We conducted a search of relevant literature on ertugliflozin in the PubMed and Web of Science databases up to 22 October 2024.

Expert opinion: Ertugliflozin reduces the incidence of composite renal endpoints, maintain eGFR, and decreases urine albumin to creatinine ratio. Cardiovascular effects of ertugliflozin are primarily demonstrated in the VERTIS CV trial. However, the cardiovascular benefits of ertugliflozin are inferior to those of empagliflozin or canagliflozin. Ertugliflozin had non-significant impact on major adverse cardiovascular events, cardiovascular death, or hospitalization for heart failure (HHF); ertugliflozin did reduce the risk of HHF, including in elderly population. Notably, ertugliflozin did not significantly reduce NT-proBNP levels in heart failure patients, while it decreased the incidence of persistent ventricular tachycardia or ventricular fibrillation events. Ertugliflozin may be beneficial for ocular diseases or neurodegenerative diseases. Adverse events associated with ertugliflozin are similar to those of previously approved SGLT2 inhibitors, although it is associated with a higher overall risk of cancer, especially renal cancer.

Introduction: Background: People with HIV (PWH) have benefited tremendously from effective antiretroviral(ARV) treatments. However, PWH are at increased risk for other viral infections transmitted in the same way as HIV (such as hepatitis C and MPox) or that are opportunistic (e.g. cytomegalovirus). These coinfections contribute significantly to morbidity and mortality among PWH and require effective treatments to optimize patient outcomes. However, their management is complicated by drug-drug interactions (DDIs) with ARVs.

Areas covered: Metabolism pathways and DDIs between approved ARVs and selected antiviral agents used for the treatment of common and clinically relevant viral coinfections are discussed. Literature review included search of published papers, conference abstracts (IAS, CROI, IDWeek, EACS, Glasgow) as well as unpublished data from approved drug prescribing information and regulatory submissions sourced from PubMed, Google, and Google Scholar available between June 30 1981 through June 1, 2024.

Expert opinion: Management of drug interactions is essential for maintaining efficacy and safety of ARV and other co-administered antiviral therapies. Longer acting agents are now available for treatment of HIV and this lengthens the period during which drug interactions may occur. Emerging novel nanoparticle-carrier targeted hepatitis C and HIV treatments may mitigate, if not eliminate, their propensity for drug-drug interactions.

Introduction: Idiosyncratic adverse drug reactions (IADRs) or drug hypersensitivity reactions (DHRs) represent a major health problem because they are unpredictable and can be severe with potential life-long or even lethal consequences. Their pathophysiology is not clear but thought to be immune mediated, supported by the significant statistical association of these reactions with specific alleles of the human leukocyte antigen (HLA) gene.

Area covered: This comprehensive update review summarizes the currently available evidence on the role of HLA gene locus in IADRs and discusses the present understanding of the pathophysiology of IADRs. We searched the available literature in PubMed and Google Scholar with no date restriction for publications on HLA and adverse drug reactions. Findings are summarized and discussed in the context of the currently available evidence.

Expert opinion: The role of the immune system in IADRs and the role of pharmacogenetic testing in this field is evident. HLA genetic testing is very promising in the management of these reactions. Many obstacles seem to prevent pharmacogenetic testing to meet its full potential including cost and health care providers' education. Further work in needed to provide more evidence and allow widespread use of pharmacogenetic testing in the clinical practice.

Introduction: Genetic load influences the therapeutic response to conventional drugs in Alzheimer's disease (AD). Pharmacogenetics (PGx) is the best option to reduce drug-drug interactions and adverse drug reactions in patients undergoing polypharmacy regimens. However, there are important limitations that make it difficult to incorporate pharmacogenetics into routine clinical practice.

Areas covered: This article analyzes the pharmacogenetic apparatus made up of pathogenic, mechanistic, metabolic, transporter, and pleiotropic genes responsible for the efficacy and safety of pharmacological treatment, the impact of genetic load on the outcome of multifactorial treatments, and practical aspects for the effective use of PGx.

Expert opinion: Over 120 genes are closely associated with AD. There is an accumulation of cerebrovascular (CVn) and neurodegenerative (ADn) genes in AD. APOE-4 carriers accumulate more deleterious genetic load related to other CVn and ADn genes, develop the disease earlier, and are at a biological disadvantage compared to APOE-4 non-carriers. CYP2D6-PMs and APOE-4 carriers are the worst responders to anti-dementia drugs. Some limitations hinder the implementation of PGx in clinical practice, including lack of pharmacogenetic information for many drugs, low number of genes in PGx screening protocols, and educational deficiencies in the medical community regarding PGx and genomic medicine.

Introduction: Drug-mediated inhibition of bile salt efflux transporters may cause liver injury. In vitro prediction of drug effects toward canalicular and/or sinusoidal efflux of bile salts from human hepatocytes is therefore a major issue, which can be addressed using liver cell-based assays.

Area covered: This review, based on a thorough literature search in the scientific databases PubMed and Web of Science, provides key information about hepatic transporters implicated in bile salt efflux, the human liver cell models available for investigating functional inhibition of bile salt efflux, the different methodologies used for this purpose, and the modes of expression of the results. Applications of the assays to drugs are summarized, with special emphasis to the performance values of some assays for predicting hepatotoxicity/cholestatic effects of drugs.

Expert opinion: Human liver cell-based assays for evaluating drug-mediated inhibition of bile acid efflux transporters face various limitations, such as the lack of method standardization and validation, the present poor adaptability to high throughput approaches, and some pitfalls with respect to interpretation of bile acid biliary excretion indexes. Hepatotoxicity of drugs is additionally likely multifactorial, highlighting that inhibition of hepatic bile salt efflux by drugs provides important, but not full, information about potential drug hepatotoxicity.

Introduction: The prevalence of polypharmacy and the increasing availability of pharmacogenetic information in clinical practice have raised the prospect of data-driven clinical decision-making when addressing the issues of drug-drug interactions and genetic polymorphisms in metabolizing enzymes. Inhibition of metabolizing enzymes in drug interactions can lead to genotype-phenotype discrepancies (phenoconversion) that reduce the relevance of individual pharmacogenetic information.

Areas covered: The aim of this review is to provide an overview of existing models of phenoconversion, and we discuss how phenoconversion models may be developed to estimate joint drug-interactions and genetic effects. Based on a literature search in PubMed, Google Scholar, and reference lists from review articles, we provide an overview of the current models of phenoconversion. The currently applied phenoconversion models are presented and discussed to predict the effects of drug-drug interactions while accounting for the pharmacogenetic status of patients.

Expert opinion: While pharmacogenetic-dose recommendations alone are most relevant for rare and extreme genotypes, phenoconversion may increase the prevalence of these phenotypes. Therefore, in polypharmacy conditions, phenoconversion assessment is especially important for personalized drug therapy.