Drug Metabolism Reviews最新文献

In the modern age, the struggle to generate appropriate bio-based materials and nano-scaled colloidal particulates for developed application domains, has already resulted in remarkable attempts in the advancement of regulated size and shape, anisotropy, and characteristics of nanostructures. The bottom-up development strategies of components are among the most important science areas throughout nanotechnology, in which the designed building blocks are often utilized to generate novel structures by random self-assembly. In biomedical applications, Janus nanoparticles (JNPs) are necessary. This is due to their effective stimulus-responsive properties, tunable structure, biocompatibility, containing two surfaces with various hydrophobic characteristics and distinct functional groups. Featuring two parts with differing hydrophobicity has been the most critical aspect of the Janus amphiphilic particles. Development of JNPs has been afforded, using imaging agents (e.g. gold (AU) for photoacoustic imaging processing (PAI), silver for surface-enhanced Raman scattering (SERS), and Fe₃O₄ and MnO₂ to magnetic resonance imaging (MRI)). It is also to be mentioned that a number of other properties become salient - properties such as integration imaging factors into JNPs (like quantum dots, fluorescent dyes), multiple imaging methods for screening and diagnosis application can indeed be accomplished. Janus nanostructures have been promising platforms for bioengineering as therapeutic carriers, drug delivery vehicles, and biosensor equipment; they may also be employed for the transport of bioactive hydrophilic and hydrophobic materials. The main production approaches and major advancement of JNPs in the biomedical sector and cancer therapy will be described in this paper.

Herbal plants typically have complex compositions and diverse mechanisms. Among them, bioactive constituents with relatively high exposure in vivo are likely to exhibit therapeutic efficacy. On the other hand, their bioavailability may be influenced by the synergistic effects of different bioactive components. Cytochrome P450 3A (CYP3A) is one of the most abundant CYP enzymes, responsible for the metabolism of 50% of approved drugs. In recent years, many therapeutic herbal constituents have been identified as CYP3A substrates. It is more evident that CYP3A inhibition derived from the herbal formula plays a critical role in improving the oral bioavailability of therapeutic constituents. CYP3A inhibition may be the mechanism of the synergism of herbal formula. In this review, we explored the multiplicity of CYP3A, summarized herbal monomers with CYP3A inhibitory effects, and evaluated herb-mediated CYP3A inhibition, thereby providing new insights into the mechanisms of CYP3A inhibition-mediated oral herb bioavailability.

The field of nanotechnology has allowed for increasing nanoparticle (NP) exposure to the male reproductive system. Certain NPs have been reported to have adverse consequences on male germ and somatic cells. Germ cells are the bridge between generations and are responsible for the transmission of genetic and epigenetic information to future generations. A number of NPs have negative impacts on male germ and somatic cells which could ultimately affect fertility or the ability to produce healthy offspring. These impacts are related to NP composition, modification, concentration, agglomeration, and route of administration. NPs can induce severe toxic effects on the male reproduction system after passing through the blood-testis barrier and ultimately damaging the spermatozoa. Therefore, understanding the impacts of NPs on reproduction is necessary. This review will provide a comprehensive overview on the current state of knowledge derived from the previous in vivo and in vitro research on effects of NPs on the male reproductive system at the genetic, cellular, and molecular levels.

The SARS-Cov-2 virus caused a high morbidity and mortality rate disease, that is the COVID-19 pandemic. Despite the unprecedented research interest in this field, the lack of specific treatments leads to severe complications in a high number of cases. Current treatment includes antivirals, corticosteroids, immunoglobulins, antimalarials, interleukin-6 inhibitors, anti-GM-CSF, convalescent plasma, immunotherapy, antibiotics, circulation support, oxygen therapy, and circulation support. Due to the limited results, until specific treatments are available, other therapeutic approaches need to be considered. The endocannabinoid system is found in multiple systems within the human body, including the immune system. Its activation can lead to beneficial results such as decreased viral entry, decreased viral replication, and a decrease in pro-inflammatory cytokines such as IL-2, IL-4, IL-6, IL-12, TNF-α, or IFN-γ. Moreover, endocannabinoid system activation can lead to an increase in anti-inflammatory cytokines, mainly represented by IL-10. Overall, the cannabinoid system can potentially reduce pulmonary inflammation, increase the immunomodulatory effect, decrease PMN infiltration, reduce fibrosis, and decrease viral replication, as well as decrease the 'cytokine storm'. Although the cannabinoid system has many mechanisms to provide certain benefits in the treatment of SARS-CoV-2 infected patients, research in this field is needed for a better understanding of the cannabinoid impact in this situation.

Developing effective strategies to confront coronavirus disease 2019 (COVID-19) has become one of the greatest concerns of the scientific community. In addition to the vast number of global mortalities due to COVID-19, since its outbreak, almost every aspect of human lives has changed one way or another. In the present review, various defensive and offensive strategies developed to confront COVID-19 are illustrated. The Administration of immune-boosting micronutrients/agents, as well as the inhibition of the activity of incompetent gatekeepers, including some host cell receptors (e.g. ACE2) and proteases (e.g. TMPRSS2), are some efficient defensive strategies. Antibody/phage therapies and specifically vaccines also play a prominent role in the enhancement of host defense against COVID-19. Nanotechnology, however, can considerably weaken the virulence of SARS-CoV-2, utilizing fake cellular locks (compounds mimicking cell receptors) to block the viral keys (spike proteins). Generally, two strategies are developed to interfere with the binding of spike proteins to the host cell receptors, either utilizing fake cellular locks to block the viral keys or utilizing fake viral keys to block the cellular locks. Due to their evolutionary conserved nature, viral enzymes, including 3CLpro, PLpro, RdRp, and helicase are highly potential targets for drug repurposing strategy. Thus, various steps of viral replication/transcription can effectively be blocked by their inhibition, leading to the elimination of SARS-CoV-2. Moreover, RNA decoy and CRISPR technologies likely offer the best offensive strategies after viral entry into the host cells, inhibiting the viral replication/assembly in the infected cells and substantially reducing the quantity of viral progeny.

Alzheimer's disease (AD) is an age-related neurodegenerative disorder, the incidence of which is climbing with ever-growing aged population, but no cure is hitherto available. The epidemiological studies unveiled that chronic intake of flavonoids was negatively associated with AD risk. Flavonoids, a family of natural polyphenols widely distributed in human daily diets, were readily conjugated by phase II drug metabolizing enzymes after absorption in vivo, and glucuronidation could occur in 1 min following intravenous administration. Recently, as many as 191 metabolites were obtained after intragastric administration of a single flavonoid, indicating that other bioactive metabolites, besides conjugates, might be formed and account for the contradiction between efficacy of flavonoids in human or animal models and low systematic exposure of flavonoid glycosides or aglycones. In this review, metabolism of complete 68 flavonoid monomers potential for AD treatment, grouped in flavonoid O-glycosides, flavonoid aglycones, flavonoid C-glycosides, flavonoid dimers, flavonolignans and prenylated flavonoids according to their common structural elements, respectively, has been systematically retrospected, summarized and discussed, including their unequivocally identified metabolites, metabolic interconversions, metabolic locations, metabolic sites (regio- or stereo-selectivity), primarily involved metabolic enzymes or intestinal bacteria, and interspecies correlations or differences in metabolism, and their bioactive metabolites and the underlying mechanism to reverse AD pathology were also reviewed, providing whole perspective about advances on extensive metabolism of diverse potent flavonoids in vivo and in vitro up to date and aiming at elucidation of mechanism of actions of flavonoids on AD or other central nervous system (CNS) disorders.

The aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor that is a member of the PER-ARNT-SIM superfamily of environmental sensors. This receptor has been a molecule of interest for many years in the field of toxicology, as it was originally discovered to mediate the toxic effects of certain environmental pollutants like benzo(a)pyrene and 2,3,7,8-tetrachlorodibenzo-p-dioxin. While all animals express this protein, there is naturally occurring variability in receptor size and responsiveness to ligand. This naturally occurring variation, particularly in mice, has been an essential tool in the discovery and early characterization of the AHR. Genetic models including congenic mice and induced mutations at the Ahr locus have proven invaluable in further understanding the role of the AHR in adaptive metabolism and TCDD-induced toxicity. The creation and examination of Ahr null mice revealed an important physiological role for the AHR in vascular and hepatic development and mediation of the immune system. In this review, we attempt to provide an overview to many of the AHR models that have aided in the understanding of AHR biology thus far. We describe the naturally occurring polymorphisms, congenic models, induced mutations at the Ahr locus and at the binding partner Ah Receptor Nuclear Translocator and chaperone, Ah receptor associated 9 loci in mice, with a brief description of naturally occurring and induced mutations in rats.

Knowledge of the metabolic stability of a new drug substance eliminated by biotransformation is essential for envisaging the pharmacokinetic parameters required for deciding drug dosing and frequency. Strategies aimed at modifying lead compounds may improve metabolic stability, thereby reducing the drug dosing frequency. Replacement of selective hydrogens with deuterium can effectively enhance the drug's metabolic stability by increasing the biological half-life. Further, cyclization, change in ring size, and chirality can substantially improve the metabolic stability of drugs. The microsomal t_1/2 approach for measuring drug in vitro intrinsic clearance by automated LC-MS/MS offers sensitive high-throughput screens with reliable data. The obtained in vitro intrinsic clearance from metabolic stability data helps predict the drug's in vivo total clearance using different scaling factors and hepatic clearance models. This review summarizes all the recent approaches and technological advancements in metabolic stability studies for narrowing down the potential lead compounds in drug discovery. Further, we summarized the potential pitfalls and assumptions made during the in vivo intrinsic clearance estimation from in vitro intrinsic clearance.

A reliable, rapid, and effective bioanalytical method is essential for the determination of the pharmacokinetic, pharmacodynamic, and toxicokinetic parameters that inform the safety and efficacy profile of investigational drugs. The overall goal of bioanalytical method development is to elucidate the procedure and operating conditions under which a method can sufficiently extract, qualify, and/or quantify the analyte(s) of interest and/or their metabolites for the intended purpose. Given the difference in the physicochemical properties of small and large molecule drugs, different strategies need to be adopted for the development of an effective and efficient bioanalytical method. Herein, we provide an overview of different sample preparation strategies, analytical platforms, as well as procedures for achieving high throughput for bioanalysis of small and large molecule drugs.

Drug-drug interactions mediated by transporters are a serious clinical concern hence a tremendous amount of work has been done on the characterization of the transporter-mediated proteins in humans and animals. The underlying mechanism for the transporter-mediated drug-drug interaction is the induction or inhibition of the transporter which is involved in the cellular uptake and efflux of drugs. Transporter of the brain, liver, kidney, and intestine are major determinants that alter the absorption, distribution, metabolism, excretion profile of drugs, and considerably influence the pharmacokinetic profile of drugs. As a consequence, transporter proteins may affect the therapeutic activity and safety of drugs. However, mounting evidence suggests that many drugs change the activity and/or expression of the transporter protein. Accordingly, evaluation of drug interaction during the drug development process is an integral part of risk assessment and regulatory requirements. Therefore, this review will highlight the clinical significance of the transporter, their role in disease, possible cause underlying the drug-drug interactions using analytical tools, and update on the regulatory requirement. The recent in-silico approaches which emphasize the advancement in the discovery of drug-drug interactions are also highlighted in this review. Besides, we discuss several endogenous biomarkers that have shown to act as substrates for many transporters, which could be potent determinants to find the drug-drug interactions mediated by transporters. Transporter-mediated drug-drug interactions are taken into consideration in the drug approval process therefore we also provided the extrapolated decision trees from in-vitro to in-vivo, which may trigger the follow-up to clinical studies.