Non-clinical pharmacokinetic profiles of rovatirelin,an orally available thyrotropin-releasing hormone analogue

1. The non-clinical pharmacokinetic profiles of rovatirelin, a novel thyrotropin-releasing hormone (TRH) analogue, were investigated in vivo and in vitro.

2. Rovatirelin orally administered to rats and dogs was rapidly absorbed and bioavailability was estimated to be 7.3 and 41.3%, respectively. The extent of plasma protein binding of rovatirelin in rats, dogs, and humans was low in all species (～15%). The permeability of rovatirelin from blood to brain (permeability-surface area) ranged from 1.04?±?0.14 to 1.29?±?0.28?μL/min/g in rats, and rovatirelin was stable in rat plasma and brain homogenates.

3. The metabolite pattern was qualitatively similar in vitro and in vivo. In animals, rovatirelin aminopentanoic acid (rovatirelin-acid), rovatirelin aminopentanone (rovatirelin-ketone), rovatirelin pyrrolidine (4S)-hydroxy (rovatirelin-OH), (thiazoylalanyl)methylpyrrolidine (TAMP), 3-(4-thiazoyl)-l-alanine (TA), and unknown metabolites were observed. In human hepatocytes, TAMP was mainly formed and no unique human metabolite was observed.

4. The radioactivity from administered [¹⁴C]rovatirelin was predominantly excreted in faeces in rats and dogs, and almost all radioactivity was recovered 168?h after administration. Absorption, brain penetration, and stability of rovatirelin in the brain were greater than for taltirelin.

5. Thus, orally administered rovatirelin is a potentially improved treatment for spinocerebellar degeneration compared with taltirelin.     

Laser‐based radiocarbon detection in the laboratory: How soon?

Research over the past 25 years and the use of accelerator mass spectrometry (AMS) have demonstrated benefits of single‐atom counting of ¹⁴C compared with scintillation monitoring of ¹⁴C radioactive decay for a multitude of applications in drug development studies. These include pharmacokinetics and metabolism studies, microdosing studies, and quantification of DNA adducts. In the last decade, the possibility of single‐atom counting using lasers has been demonstrated, providing the possibility of simplified laboratory‐based systems, which can equal or excel AMS sensitivity and provide scintillation system convenience without high levels of radioactivity. To achieve the required sensitivity, optical storage cavities have been used to enhance the laser interaction of the low densities of radiocarbon present. Two types of laser technologies have been used‐cavity ring‐down spectroscopy (CRDS) and intracavity opto‐galvanic spectroscopy (ICOGS). Problems to be overcome to achieve routine use have included separation of the ¹⁴C signal from backgrounds, achievement of acceptable precision and accuracy, reduction of measurement times for small samples, and improvement in the ease of use for the operator. Both technologies have achieved impressive results to date using samples of order 1 mg with CRDS and 10 μg with ICOGS. Commercial development is the next step.     

Precise prediction of activators for the human constitutive androstane receptor using structure-based three-dimensional quantitative structure–activity relationship methods

The constitutive androstane receptor (CAR, NR1I3) regulates the expression of numerous drug-metabolizing enzymes and transporters. The upregulation of various enzymes, including CYP2B6, by CAR activators is a critical problem leading to clinically severe drug–drug interactions (DDIs). To date, however, few effective computational approaches for identifying CAR activators exist. In this study, we aimed to develop three-dimensional quantitative structure–activity relationship (3D-QSAR) models to predict the CAR activating potency of compounds emerging in the drug-discovery process. Models were constructed using comparative molecular field analysis (CoMFA) based on the molecular alignments of ligands binding to CAR, which were obtained from ensemble ligand-docking using 28 compounds as a training set. The CoMFA model, modified by adding a lipophilic parameter with calculated logD_7.4 (S+logD_7.4), demonstrated statistically good predictive ability (r² = 0.99, q² = 0.74). We also confirmed the excellent predictability of the 3D-QSAR model for CAR activation (r²_pred = 0.71) using seven compounds as a test set for external validation. Collectively, our results indicate that the 3D-QSAR model developed in this study provides precise prediction of CAR activating potency and, thus, should be useful for selecting drug candidates with minimized DDI risk related to enzyme-induction in the early drug-discovery stage.     

Novel strategies for microdose studies using non-radiolabeled compounds

Microdose studies using non-radiolabeled compounds enable assessment of the clinical pharmacokinetics of drug candidates in humans without the need to synthesize radiolabeled compounds. We have demonstrated that the quantification limits of many drugs measured by LC-MS/MS are low enough to allow estimation of their pharmacokinetic parameters following administration of a microdose. Our previous microdose studies with LC-MS/MS demonstrated the linear pharmacokinetics of fexofenadine between microdoses and therapeutic doses. We also obtained time profiles of plasma concentrations of nicardipine and its multiple metabolites following administration of a microdose. A significant advantage of using non-radiolabeled compounds is the ability to perform cassette microdose studies. By administering multiple drug candidates to the same subject, we can select compounds with appropriate pharmacokinetic properties simultaneously. We can also clarify major factors dominating the pharmacokinetics of drug candidates by cocktail microdosing of the test compounds and probe substrates with or without specific inhibitors for enzymes/transporters.     

基于体内ADME过程和网络药理学的中药现代研究思路

网络药理学应用到中药研究中,有利于阐释中药药效物质基础和作用机制,提高中药新药的研发水平,但是,鉴于中药有效物质的复杂性特点,进行体内过程分析,明确进入体内的成分,是将网络药理学应用于中药研究的前提。为此,提出体内ADME过程与网络药理学相结合的中药现代研究思路。     

Do Interactions Between Gut Ecology and Environmental Chemicals Contribute to Obesity and Diabetes?

Background: Gut microbiota are important factors in obesity and diabetes, yet little is known about their role in the toxicodynamics of environmental chemicals, including those recently found to be obesogenic and diabetogenic.Objectives: We integrated evidence that independently links gut ecology and environmental chemicals to obesity and diabetes, providing a framework for suggesting how these environmental factors may interact with these diseases, and identified future research needs.Methods: We examined studies with germ-free or antibiotic-treated laboratory animals, and human studies that evaluated how dietary influences and microbial changes affected obesity and diabetes. Strengths and weaknesses of studies evaluating how environmental chemical exposures may affect obesity and diabetes were summarized, and research gaps on how gut ecology may affect the disposition of environmental chemicals were identified.Results: Mounting evidence indicates that gut microbiota composition affects obesity and diabetes, as does exposure to environmental chemicals. The toxicology and pharmacology literature also suggests that interindividual variations in gut microbiota may affect chemical metabolism via direct activation of chemicals, depletion of metabolites needed for biotransformation, alteration of host biotransformation enzyme activities, changes in enterohepatic circulation, altered bioavailability of environmental chemicals and/or antioxidants from food, and alterations in gut motility and barrier function.Conclusions: Variations in gut microbiota are likely to affect human toxicodynamics and increase individual exposure to obesogenic and diabetogenic chemicals. Combating the global obesity and diabetes epidemics requires a multifaceted approach that should include greater emphasis on understanding and controlling the impact of interindividual gut microbe variability on the disposition of environmental chemicals in humans.     

ADME/Tox体外模型结合LC/MS法在中药研究中的应用

由于中药及其复方化学成分的复杂性和作用环节及作用靶点的多重性。要完全阐明中药作用的物质基础和作用机制是有困难的,利用ADME/Tox体外模型及LC/MS等现代分析方法对中药进行研究有其特点和优势,目前对中药的ADME/Tox体外模型还没有建立起一个完整的实验体系,本文对国内外常用于ADME/Tox研究的体外模型进行了综述,以期为中药的ADME/Tox体外研究提供一个思路。     

系统生物学在中药ADME性质研究中的应用

本文从中医的研究角度综述了系统生物学的定义、研究框架、范围和方法论特点, 并以PBPK和PBPD 研究为实例, 详述了系统生物学方法论在药学研究中的最新应用和进展, 阐明了系统生物学是还原论基础上的整体论。中医药是中医整体辩证理论指导下的复杂体系, 拟乘系统生物学之势将面对诸多基础问题的挑战, 然而中药ADME 性质的阐明将成为中医药系统生物学研究的基石, 从而将分子水平和整体水平有力地衔接起来。本文中同时简略地综述了作者研究组在该领域的有益尝试, 结果表明中药的早期ADME性质研究方法将是揭开中药之谜并过渡到系统生物学水平的有力手段。