Tritium: a coming of age for drug discovery and development ADME studies

Owing to recent developments in tritium chemistry and analysis, high‐quality tritium‐labelled drugs can now be prepared simply, cheaply and in timescales commensurate with those needed for rapid drug discovery in adsorption, distribution, metabolism and excretion (ADME) projects. Such ³H‐labelled drugs are enabling high‐quality decision‐making at key points in the drug discovery process, thus ensuring more effective research projects, a key issue in commercial success. In addition, tritium‐labelled compounds continue to play a significant role in ADME studies later in the pharmaceutical development process. This is especially so for highly potent and hence low‐dose agents, for drugs with complex structures and for those compounds that undergo molecular fragmentation as a result of metabolism.     

秀丽隐杆线虫在医药学领域的应用和进展

模式生物秀丽隐杆线虫 (Caenorhabditis elegans) 对基础生物学研究贡献卓著。随着功能基因组时代的到来, 线虫被视为可借以探明人类致病基因或致病相关因子, 寻找可能的药物靶点的强大工具。这得益于线虫的丰富的可利用生物学信息, 灵活多样的遗传学可操作性, 简易的培养维持条件, 尤其是其独特的生理特点适合于大规模化学药物的体内筛选或全基因组功能研究。本文将从新药研发的角度总结线虫的特点, 与人类基因的同源性, 讨论以线虫为技术平台的药物研发主要方法, 以及成功案例, 并探讨线虫在医药学领域的发展热点。     

FT-IR spectroscopy: a powerful tool in pharmacology

In the present work we report a Fourier Transform Infrared (FT-IR) analysis performed on rat encephalon samples in the CH---OH vibrational stretching region (2400–3800) cm⁻¹, in order to reveal the presence of a very diffuse commercial benzodiazepine: VALIUM®. The comparison between the spectral features of normal brain and the ones of samples with administrated substance has unambiguously showed that the CH stretching region seems not to suffer from any change for the pharmacological treatment, instead the OH band is strongly modified probably due to the presence of a new spectral contribution characteristic of diazepam molecule.     

Inter-ethnic differences in drug response: Implications for drug development and complying with drug regulation

Abstract

The two key components of the pharmacology of a drug—dose–concentration (pharmacokinetic) and/or concentration–response (pharmacodynamic) relationships—are often influenced by genetic variations. These account for a substantial fraction of variability in dose–response or drug response, not only between individuals, but also between different ethnic groups. The approval of ‘BiDil’ for the treatment of cardiac failure in self-identified black patients is a spectacular example of inter-ethnic differences in drug response and regulatory awareness of ethnicity of the study population. Drug development programs are increasingly undertaken globally to reduce costs, shorten timeframes, and address issues concerning global prescribing. Regulatory authorities have responded to this globalization of drug development by promulgating guidelines that recommend sponsors of new drugs to explore the role of genetic variations, and potential differences in drug response, between different ethnic populations. They may refuse to accept an application, or require bridging studies, when such differences are anticipated but not adequately addressed. These bridging studies may include (i) pharmacokinetic studies, (ii) pharmacodynamic studies, (iii) dose–response studies, and/or (iv) in extreme cases, pivotal phase III studies in order to extrapolate efficacy and/or safety data from one population to another.     

Absorption,distribution, metabolism and excretion of molidustat in healthy participants

The absorption, distribution, metabolism and excretion of molidustat were investigated in healthy male participants. In study 1, a mass balance study, radiolabelled molidustat 25 mg (3.57 MBq) was administered as an oral solution (n = 4). Following rapid absorption, molidustat‐related radioactivity was predominantly distributed in plasma rather than in red blood cells. The total recovery of the administered radioactivity was 97.0%, which was mainly excreted renally (90.7%). Metabolite M‐1, produced by N‐glucuronidation, was the dominant component in plasma (80.2% of the area under the concentration‐time curve for total radioactivity) and was primarily excreted via urine (~85% of dose). Only minor amounts of unchanged molidustat were excreted in urine (~4%) and faeces (~6%). Study 2 investigated the absolute bioavailability and pharmacodynamics of molidustat (part 1, n = 12; part 2, n = 16). Orally administered molidustat immediate release tablets had an absolute bioavailability of 59%. Following intravenous administration (1, 5 and 25 mg), total body clearance of molidustat was 28.7‐34.5 L/h and volume of distribution at steady state was 39.3‐50.0 L. All doses of molidustat transiently elevated endogenous erythropoietin levels, irrespective of the route of administration. Molidustat was considered safe and well tolerated at the administered doses.     

Quantum dots: a powerful tool for understanding the intricacies of nanoparticle-mediated drug delivery

Nanoparticle-mediated drug delivery (NMDD) is an emerging research area that seeks to address many of the pharmacokinetic issues encountered with traditional systemically administered drug therapies. Although the field is still in its infancy, recent research has already highlighted the potential for improved drug delivery and targeted therapeutics; however, the real promise lies in combining drug therapy with diagnostic imaging, nucleic acid delivery/gene therapy and/or biosensing applications all in one engineered nanoparticle vector. In this review, the authors discuss the unique contributions that luminescent semiconductor nanocrystals or quantum dots (QDs) offer for NMDD, how they can function as a powerful nanoscale platform to understand this process at its most basic level, and even provide drug-related properties in certain circumstances. Selected examples from the current literature are utilized to describe both their potential and the contributions they have already made towards the design and implementation of NMDD vectors. Important related issues such as QD biofunctionalization and toxicity are also discussed. The paper concludes with a perspective of how this field can be expected to develop in the future.     

体内重组工程:功能基因组研究中的一种新武器

基于微生物内源重组系统建立的体内重组工程已成为对生物体内基因功能研究的主要技术，通过基因敲除与嵌入，或大片段DNA的缺失与插入，然后根据生物体表型的变化可以确定该基因或基因簇在体内行使的功能。随着对噬菌体重组系统的认识。发展出了一种新的重组技术可以更简便、更精确、更快速地进行体内基因操作。本文试图就两种重组工程的原理与应用做一综述。     

HPLC-API/MS/MS: a powerful tool for integrating drug metabolism into the drug discovery process

HPLC combined with atmospheric pressure ionization (API) mass spectrometry (MS) has become a very useful tool in the pharmaceutical industry. The technique of HPLC-API/MS/MS is becoming very important for both drug discovery and drug development programs. In the drug discovery area, it has three major uses: (1) rapid, quantitative method development, (2) metabolite identification, and (3) multi-drug analysis. The sensitivity of the API source and the selectivity provided by tandem mass spectrometry (MS/MS) enable rapid, quantitative method development for drugs in plasma. Early information on the metabolism of candidate drugs can guide structural modifications, thereby improving the activity and/or bioavailability.     

Biospecific interaction analysis: a tool for drug discovery and development

The recent development of surface plasmon resonance (SPR)-based biosensor technologies for biospecific interaction analysis (BIA) enables the monitoring of a variety of molecular reactions in real-time. The biomolecular interactions occur at the surface of a flow cell of a sensor chip between a ligand immobilized on the surface and an injected analyte. SPR-based BIA offers many advantages over most of the other methodologies available for the study of biomolecular interactions, including full automation, no requirement for labeling, and the availability of a large variety of activated sensor chips that allow immobilization of DNA, RNA, proteins, peptides and cells. The assay is rapid and requires only small quantitities of both ligand and analyte in order to obtain informative results. In addition, the sensor chip can be re-used many times, leading to low running costs. Aside from the analysis of all possible combinations of peptide, protein, DNA and RNA interactions, this technology can also be used for screening of monoclonal antibodies and epitope mapping, analysis of interactions between low molecular weight compounds and proteins or nucleic acids, interactions between cells and ligands, and real-time monitoring of gene expression. Applications of SPR-based BIA in medicine include the molecular diagnosis of viral infections and genetic diseases caused by point mutations. Future perspectives include the combinations of SPR-based BIA with mass spectrometry, the use of biosensors in proteomics, and the application of this technology to design and develop efficient drug delivery systems.     

Pharmacokinetic properties and drug interactions of apigenin,a natural flavone

Introduction: Apigenin, a natural flavone, is widely distributed in plants such as celery, parsley and chamomile. It is present principally as glycosylated in nature. Higher intake of apigenin could reduce the risk of chronic diseases. It has gained particular interest in recent years as a beneficial, health-promoting agent with low intrinsic toxicity.

Areas covered: This review summarizes and the absorption, distribution, metabolism and excretion (ADME) properties of apigenin, and drug-drug interaction of apigenin.

Expert opinion: Since apigenin is a bioactive plant flavone and is widely distributed in common food, its consumption through the diet is recommended. Apigenin-enriched drugs are better for some chronic diseases, but may affect animal and human health if present in the daily diet. Dietary or therapeutic apigenin has value as a good cellular regulator in cancer, especially cancers of the gastrointestinal tract. Due to apigenin’s limitations on absorption and bioavailability, novel carriers would need to be developed to enhance the oral bioavailability of apigenin. Further research about its ADME properties and drug-drug interactions are needed before apigenin can be brought to clinical trials.     

Iodine‐125‐terbutaline (125ITB): a new β2‐adrenoceptor probe for lung imaging

Development of a selective β₂‐adrenoceptor tracer for single photon emission tomography is important for imaging of the lungs. Iodine‐125‐terbutaline (¹²⁵ITB) was prepared by the reaction of terbutaline with iodine‐125 in the presence of chloramine‐T as the oxidizing agent. The reaction was completed by incubation of the reaction mixture at 70°C for 15 minutes at pH 7. The biodistribution study in mice indicated the ability of the tracer to bind β‐adrenoceptors in lungs, liver, heart, and spleen. The localization of the tracer in the lungs was high (85%/g at 60 minutes post‐injection) and the highest lung/blood/g ratio was 19.8% at 60 minutes post‐injection. The selectivity of the tracer for the β₂‐adrenoceptor was examined by blocking with both β₁ and β₂‐adrenoceptor selective antagonists. The results showed reduction of both heart and lung uptake of the ¹²⁵ITB tracer, indicating a moderate (not absolute) selectivity for the β₂‐adrenoceptor. Copyright © 2012 John Wiley & Sons, Ltd.     

Characterization of preclinical in vitro and in vivo ADME properties and prediction of human PK using a physiologically based pharmacokinetic model for YQA‐14, a new dopamine D3 receptor antagonist candidate for treatment of drug addiction

YQA‐14 is a novel and selective dopamine D3 receptor antagonist, with potential for the treatment of drug addiction. However, earlier compounds in its structural class tend to have poor oral bioavailability. The objectives of this study were to characterize the preclinical absorption, distribution, metabolism and excretion (ADME) properties and pharmacokinetics (PK) of YQA‐14, then to simulate the clinical PK of YQA‐14 using a physiologically based pharmacokinetics (PBPK) model to assess the likelihood of developing YQA‐14 as a clinical candidate. For human PK prediction, PBPK models were first built in preclinical species, rats and dogs, for validation purposes. The model was then modified by input of human in vitro ADME data obtained from in vitro studies. The study data showed that YQA‐14 is a basic lipophilic compound, with rapid absorption (T_max ~ 1 h) in both rats and dogs. Liver microsomal clearances and in vivo clearances were moderate in rats and dogs consistent with the moderate bioavailability observed in both species. The PBPK models built for rats and dogs simulated the observed PK data well in both species. The PBPK model refined with human data predicted that YQA‐14 would have a clearance of 8.0 ml/min/kg, a volume distribution of 1.7 l/kg and a bioavailability of 16.9%. These acceptable PK properties make YQA‐14 an improved candidate for further research and development as a potential dopamine D3R antagonism for the treatment of drug addiction in the clinic. Copyright © 2014 John Wiley & Sons, Ltd.     

Imaging Mass Spectrometry (IMS) for drug discovery and development survey: Results on methods,applications and regulatory compliance

Imaging mass spectrometry (IMS) is increasingly used for drug discovery and development to understand target enagement, tissue distribution, drug toxicity, and disease mechanisms, etc. However, this is still a relatively new technique that requires further development validation before it will be an acceptable technique to support regulated development of new drugs. Thus, best practices will need to be established to build more confidence and gain wider acceptance by the scientific community, pharmaceutical industry, and regulatory authorities. The Imaging Mass Spectrometry Society (IMSS) and the Japan Association for Imaging Mass Spectrometry (JAIMS) have conducted a thorough survey to gather information on the current state of IMS and to identify key issues. The survey was sent to researchers or managers in the position who are currently using IMS techniques in support of their drug discovery and development efforts and/or who plan to use such tools as best practices are established. The survey probes questions related to details regarding technical aspects of IMS, which includes data acquisition, data analysis and quantitation, data integrity, reporting, applications, and regulatory concerns. This international survey was conducted online through the Survey Monkey (https://www.surveymonkey.com) in both English and Japanese from September 14 through September 30, 2020.     

自乳化药物传递系统的研究进展

本文对近几年国内外有关自乳化药物传递系统的特点、吸收机制、组成、影响因素及其在药剂学方面的应用进行了归纳和分析。自乳化药物传递系统可显著地提高难溶性或亲脂性药物口服生物利用度，具有广阔的发展前景。     

Physiologically based pharmacokinetic modeling as a tool for drug development

Since the pioneering work of Haggard and Teorell in the first half of the 20th century, and of Bischoff and Dedrick in the late 1960s, physiologically based pharmacokinetic (PBPK) modeling has gone through cycles of general acceptance, and of healthy skepticism. Recently, however, the trend in the pharmaceuticals industry has been away from PBPK models. This is understandable when one considers the time and effort necessary to develop, test, and implement a typical PBPK model, and the fact that in the present-day environment for drug development, efficacy and safety must be demonstrated and drugs brought to market more rapidly. Although there are many modeling tools available to the pharmacokineticist today, many of which are preferable to PBPK modeling in most circumstances, there are several situations in which PBPK modeling provides distinct benefits that outweigh the drawbacks of increased time and effort for implementation. In this Commentary, we draw on our experience with this modeling technique in an industry setting to provide guidelines on when PBPK modeling techniques could be applied in an industrial setting to satisfy the needs of regulatory customers. We hope these guidelines will assist researchers in deciding when to apply PBPK modeling techniques. It is our contention that PBPK modeling should be viewed as one of many modeling tools for drug development.     

Molecular imaging with SPECT as a tool for drug development

Molecular imaging techniques are increasingly being used as valuable tools in the drug development process. Radionuclide-based imaging modalities such as single-photon emission computed tomography (SPECT) and positron emission tomography (PET) have proven to be useful in phases ranging from preclinical development to the initial stages of clinical testing. The high sensitivity of these imaging modalities makes them particularly suited for exploratory investigational new drug (IND) studies as they have the potential to characterize in vivo pharmacokinetics and biodistribution of the compounds using only a fraction of the intended therapeutic dose (microdosing). This information obtained at an early stage of clinical testing results in a better selection among promising drug candidates, thereby increasing the success rate of agents entering clinical trials and the overall efficiency of the process. In this article, we will review the potential applications of SPECT imaging in the drug development process with an emphasis on its applications in exploratory IND studies.     

Fluorine magnetic resonance in vivo: a powerful tool in the study of drug distribution and metabolism

Magnetic resonance (MR) provides an attractive non-invasive way of studying drug distribution in vivo. Widespread occurrence of fluorine in medicinal compounds, and its favourable MR properties, make it an effective probe for drug absorption, distribution, metabolism and excretion (ADME) studies. We discuss practicalities of detection and localization, and when (19)F MR would add value in a clinical trial, exemplified by deployments in oncology and psychiatry, where it is a practical way of demonstrating chronic brain accumulation directly. Limitations are emphasized to minimize failure risk, for example, inadequate sensitivity relative to tissue drug concentrations. The review anticipates increasing clinical (19)F MR as high field human scanners become widespread, and requirements to demonstrate mechanisms underlying clinical effects become more pressing.