scholarly journals Relevance of In Vitro Metabolism Models to PET Radiotracer Development: Prediction of In Vivo Clearance in Rats from Microsomal Stability Data

2019 ◽  
Vol 12 (2) ◽  
pp. 57 ◽  
Author(s):  
Daniela Schneider ◽  
Angela Oskamp ◽  
Marcus Holschbach ◽  
Bernd Neumaier ◽  
Andreas Bauer ◽  
...  
Keyword(s):  
Liver Microsomes ◽  
In Vitro Metabolism ◽  
Amount Of Substance ◽  
Positron Emission ◽  
Clearance Prediction ◽  
Pet Radiotracers ◽  
Stability Data ◽  
In Vitro Data

The prediction of in vivo clearance from in vitro metabolism models such as liver microsomes is an established procedure in drug discovery. The potentials and limitations of this approach have been extensively evaluated in the pharmaceutical sector; however, this is not the case for the field of positron emission tomography (PET) radiotracer development. The application of PET radiotracers and classical drugs differs greatly with regard to the amount of substance administered. In typical PET imaging sessions, subnanomolar quantities of the radiotracer are injected, resulting in body concentrations that cannot be readily simulated in analytical assays. This raises concerns regarding the predictability of radiotracer clearance from in vitro data. We assessed the accuracy of clearance prediction for three prototypical PET radiotracers developed for imaging the A1 adenosine receptor (A1AR). Using the half-life (t1/2) approach and physiologically based scaling, in vivo clearance in the rat model was predicted from microsomal stability data. Actual clearance could be accurately predicted with an average fold error (AFE) of 0.78 and a root mean square error (RMSE) of 1.6. The observed slight underprediction (1.3-fold) is in accordance with the prediction accuracy reported for classical drugs. This result indicates that the prediction of radiotracer clearance is possible despite concentration differences of more than three orders of magnitude between in vitro and in vivo conditions. Consequently, in vitro metabolism models represent a valuable tool for PET radiotracer development.

Presence of enniatin B and its hepatic metabolites in plasma and liver samples from broilers and eggs from laying hens

2014 ◽  
Vol 7 (2) ◽  
pp. 167-175 ◽  
Author(s):  
L. Ivanova ◽  
C.K. Fæste ◽  
E. Van Pamel ◽  
E. Daeseleire ◽  
A. Callebaut ◽  
...  
Keyword(s):  
Liver Microsomes ◽  
Serum Samples ◽  
Cytotoxic Effects ◽  
Spectrometric Data ◽  
Metabolite Profiles ◽  
Vitro Data ◽  
In Vitro Data ◽  
Animal Consumption

Enniatins, a large group of cyclodepsipeptides, are widely distributed contaminants of different crops intended for human and animal consumption. Enniatin B is one of the principal analogues in species of the genus Fusarium, known to have ionophoric, antibiotic, and insecticidal activity. Regardless of considerable cytotoxic effects observed in vitro, enniatins have been characterised as compounds with low acute toxicity in vivo. The biotransformation of enniatin B has previously been elucidated in liver microsomes, and 12 different metabolites (M1 to M12) have been reported. In order to provide a better basis for understanding the potential toxic effects in humans and animals, different samples (eggs, livers, plasma) from two different feeding studies have been analysed for the presence of enniatin B and its hepatic metabolites. The earlier reported metabolite M11, and a novel metabolite (designated M13), were dominant in liver samples from enniatin B exposed broilers. The peak area corresponding to the sodiated molecular ion of M11 was approximately 2.5 times larger than that of parent enniatin B in liver samples collected after one week of exposure. The same metabolites were also present in serum samples. In egg samples, only metabolites M13 and M4 were detected. The comparison of mass spectrometric data of M13 and enniatin B suggested that M13 is a monohydroxylated metabolite. The hepatic biotransformation of enniatin B was also investigated in vitro in chicken microsomes demonstrating good correlation with the metabolite profiles in the chicken samples. The results of the present study demonstrated an extensive biotransformation of enniatin B in vivo confirming previously reported in vitro data.

scholarly journals Synthesis and In Vitro Evaluation of 8-Pyridinyl-Substituted Benzo[e]imidazo[2,1-c][1,2,4]triazines as Phosphodiesterase 2A Inhibitors

Molecules ◽  
2019 ◽  
Vol 24 (15) ◽  
pp. 2791 ◽  
Author(s):  
Ritawidya ◽  
Ludwig ◽  
Briel ◽  
Brust ◽  
Scheunemann
Keyword(s):  
Potent Inhibitor ◽  
Liver Microsomes ◽  
Emission Tomography ◽  
Inhibitory Potency ◽  
Positron Emission ◽  
Neuropsychiatric Diseases ◽  
Further Development ◽  
The Brain

Phosphodiesterase 2A (PDE2A) is highly expressed in distinct areas of the brain, which are known to be related to neuropsychiatric diseases. The development of suitable PDE2A tracers for Positron Emission Tomography (PET) would permit the in vivo imaging of the PDE2A and evaluation of disease-mediated alterations of its expression. A series of novel fluorinated PDE2A inhibitors on the basis of a Benzoimidazotriazine (BIT) scaffold was prepared leading to a prospective inhibitor for further development of a PDE2A PET imaging agent. BIT derivatives (BIT1–9) were obtained by a seven-step synthesis route, and their inhibitory potency towards PDE2A and selectivity over other PDEs were evaluated. BIT1 demonstrated much higher inhibition than other BIT derivatives (82.9% inhibition of PDE2A at 10 nM). BIT1 displayed an IC50 for PDE2A of 3.33 nM with 16-fold selectivity over PDE10A. This finding revealed that a derivative bearing both a 2-fluoro-pyridin-4-yl and 2-chloro-5-methoxy-phenyl unit at the 8- and 1-position, respectively, appeared to be the most potent inhibitor. In vitro studies of BIT1 using mouse liver microsomes (MLM) disclosed BIT1 as a suitable ligand for 18F-labeling. Nevertheless, future in vivo metabolism studies are required.

scholarly journals Determination of [11C]PBR28 Binding Potential in vivo: A First Human TSPO Blocking Study

2014 ◽  
Vol 34 (6) ◽  
pp. 989-994 ◽  
Author(s):  
David R Owen ◽  
Qi Guo ◽  
Nicola J Kalk ◽  
Alessandro Colasanti ◽  
Dimitra Kalogiannopoulou ◽  
...  
Keyword(s):  
Volume Of Distribution ◽  
Translocator Protein ◽  
Binding Potential ◽  
Healthy Human ◽  
Positron Emission ◽  
Dose Dependent ◽  
In Vitro Data

Positron emission tomography (PET) targeting the 18 kDa translocator protein (TSPO) is used to quantify neuroinflammation. Translocator protein is expressed throughout the brain, and therefore a classical reference region approach cannot be used to estimate binding potential ( BP ND). Here, we used blockade of the TSPO radioligand [11C]PBR28 with the TSPO ligand XBD173, to determine the non-displaceable volume of distribution ( V ND), and hence estimate the BP ND. A total of 26 healthy volunteers, 16 high-affinity binders (HABs) and 10 mixed affinity binders (MABs) underwent a [11C]PBR28 PET scan with arterial sampling. Six of the HABs received oral XBD173 (10 to 90 mg), 2 hours before a repeat scan. In XBD173-dosed subjects, V ND was estimated via the occupancy plot. Values of BP ND for all subjects were calculated using this V ND estimate. Total volume of distribution ( V T) of MABs (2.94 ± 0.31) was lower than V T of HABs (4.33 ± 0.29) ( P<0.005). There was dose-dependent occupancy of TSPO by XBD173 (ED50 = 0.34 ± 0.13 mg/kg). The occupancy plot provided a V ND estimate of 1.98 (1.69, 2.26). Based on these V ND estimates, BP ND for HABs is approximately twice that of MABs, consistent with predictions from in vitro data. Our estimates of [11C]PBR28 V ND and hence BP ND in the healthy human brain are consistent with in vitro predictions. XBD173 blockade provides a practical means of estimating V ND for TSPO targeting radioligands.

scholarly journals How to Choose In Vitro Systems to Predict In Vivo Drug Clearance: A System Pharmacology Perspective

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Lei Wang ◽  
ChienWei Chiang ◽  
Hong Liang ◽  
Hengyi Wu ◽  
Weixing Feng ◽  
...  
Keyword(s):  
Large Scale ◽  
Relevant Information ◽  
Drug Clearance ◽  
In Vitro Metabolism ◽  
System Pharmacology ◽  
Clearance Prediction ◽  
In Vitro Systems ◽  
Baculovirus System

The use of in vitro metabolism data to predict human clearance has become more significant in the current prediction of large scale drug clearance for all the drugs. The relevant information (in vitro metabolism data and in vivo human clearance values) of thirty-five drugs that satisfied the entry criteria of probe drugs was collated from the literature. Then the performance of different in vitro systems includingEscherichia colisystem, yeast system, lymphoblastoid system and baculovirus system is compared after in vitro-in vivo extrapolation. Baculovirus system, which can provide most of the data, has almost equal accuracy as the other systems in predicting clearance. And in most cases, baculovirus system has the smaller CV in scaling factors. Therefore, the baculovirus system can be recognized as the suitable system for the large scale drug clearance prediction.

scholarly journals In Vitro Phase I Metabolism of the Recently Emerged Synthetic MDMB-4en-PINACA and Its Detection in Human Urine Samples

2020 ◽  
Author(s):  
Yeter Erol Ozturk ◽  
Oya Yeter
Keyword(s):  
Double Bond ◽  
High Resolution Mass Spectrometry ◽  
Parent Compound ◽  
Liver Microsomes ◽  
Ester Hydrolysis ◽  
In Vitro Metabolism ◽  
Urine Samples ◽  
Total N

Abstract MDMB-4en-PINACA (methyl (S)-3,3-dimethyl-2-(1-(pent-4-en-1-yl)-1H-indazole-3-carboxamido)butanoate) is a recently emerged synthetic cannabinoid in Turkey. MDMB-4en-PINACA was detected in herbal material investigated by the Council of Forensic Medicine, Istanbul Narcotics Department in Turkey in April 2019. MDMB-4en-PINACA was added to the drug abuse list and quickly reported in biological samples after its first detection. In this study, the in vitro metabolism of MDMB-4en-PINACA was investigated by using a pooled human liver microsomes (HLMs) assay and liquid chromatography–high-resolution mass spectrometry (LC–HRMS). MDMB-4en-PINACA (5 μmol/L) was incubated with HLMs for up to 1 h, and the metabolites were identified using LC–HRMS and software-assisted data mining. The in vivo metabolism was investigated by the analysis of 22 authentic urine samples and compared to the data received from the in vitro metabolism study. Less than 7.5% of the MDMB-4en-PINACA parent compound remained after the 1 h incubation. We identified 14 metabolites, which were formed via double bond oxidation, ester hydrolysis, N-dealkylation, hydroxylation, dehydrogenation and further oxidation to N-pentanoic acid or a combination of these reactions in vitro. In 10 urine samples (total n = 22), MDMB-4en-PINACA was detected as the parent drug. Three of the identified main metabolites, double bond oxidation in combination with ester hydrolysis and hydroxylation metabolite (M3), MDMB-4en-PINACA butanoic acid (M14) and monohydroxypentyl-MDMB-4en-PINACA (M12), were suggested as suitable urinary markers. In vitro screening of 2,150 authentic urine samples for these identified MDMB-4en-PINACA metabolites resulted in 56 cases of confirmed MDMB-4en-PINACA consumption (2.6%).

scholarly journals Non-Invasive in vivo Imaging in Small Animal Research

2006 ◽  
Vol 28 (4) ◽  
pp. 127-139 ◽  
Author(s):  
V. Koo ◽  
P. W. Hamilton ◽  
K. Williamson
Keyword(s):  
Experimental Studies ◽  
Small Animal ◽  
Non Invasive ◽  
Positron Emission ◽  
Small Animal Models ◽  
Magnetic Resonance Imaging Mri ◽  
Animal Care ◽  
In Vitro Data

Non-invasive real time in vivo molecular imaging in small animal models has become the essential bridge between in vitro data and their translation into clinical applications. The tremendous development and technological progress, such as tumour modelling, monitoring of tumour growth and detection of metastasis, has facilitated translational drug development. This has added to our knowledge on carcinogenesis. The modalities that are commonly used include Magnetic Resonance Imaging (MRI), Computed Tomography (CT), Positron Emission Tomography (PET), bioluminescence imaging, fluorescence imaging and multi-modality imaging systems. The ability to obtain multiple images longitudinally provides reliable information whilst reducing animal numbers. As yet there is no one modality that is ideal for all experimental studies. This review outlines the instrumentation available together with corresponding applications reported in the literature with particular emphasis on cancer research. Advantages and limitations to current imaging technology are discussed and the issues concerning small animal care during imaging are highlighted.

scholarly journals Development of a blood sample detector for multi-tracer positron emission tomography using gamma spectroscopy

2019 ◽  
Vol 6 (1) ◽  
Author(s):  
Carlos Velasco ◽  
Adriana Mota-Cobián ◽  
Jesús Mateo ◽  
Samuel España
Keyword(s):  
Positron Emission Tomography ◽  
Blood Sample ◽  
Pet Imaging ◽  
Spectroscopic Analysis ◽  
Gamma Spectroscopy ◽  
Emission Tomography ◽  
Blood Samples ◽  
Positron Emission

Abstract Background Multi-tracer positron emission tomography (PET) imaging can be accomplished by applying multi-tracer compartment modeling. Recently, a method has been proposed in which the arterial input functions (AIFs) of the multi-tracer PET scan are explicitly derived. For that purpose, a gamma spectroscopic analysis is performed on blood samples manually withdrawn from the patient when at least one of the co-injected tracers is based on a non-pure positron emitter. Alternatively, these blood samples required for the spectroscopic analysis may be obtained and analyzed on site by an automated detection device, thus minimizing analysis time and radiation exposure of the operating personnel. In this work, a new automated blood sample detector based on silicon photomultipliers (SiPMs) for single- and multi-tracer PET imaging is presented, characterized, and tested in vitro and in vivo. Results The detector presented in this work stores and analyzes on-the-fly single and coincidence detected events. A sensitivity of 22.6 cps/(kBq/mL) and 1.7 cps/(kBq/mL) was obtained for single and coincidence events respectively. An energy resolution of 35% full-width-half-maximum (FWHM) at 511 keV and a minimum detectable activity of 0.30 ± 0.08 kBq/mL in single mode were obtained. The in vivo AIFs obtained with the detector show an excellent Pearson’s correlation (r = 0.996, p < 0.0001) with the ones obtained from well counter analysis of discrete blood samples. Moreover, in vitro experiments demonstrate the capability of the detector to apply the gamma spectroscopic analysis on a mixture of 68Ga and 18F and separate the individual signal emitted from each one. Conclusions Characterization and in vivo evaluation under realistic experimental conditions showed that the detector proposed in this work offers excellent sensibility and stability. The device also showed to successfully separate individual signals emitted from a mixture of radioisotopes. Therefore, the blood sample detector presented in this study allows fully automatic AIFs measurements during single- and multi-tracer PET studies.

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