scholarly journals Species Differences in Microsomal Metabolism of Xanthine-Derived A1 Adenosine Receptor Ligands

2021 ◽  
Vol 14 (3) ◽  
pp. 277
Author(s):  
Daniela Schneider ◽  
Dirk Bier ◽  
Marcus Holschbach ◽  
Andreas Bauer ◽  
Bernd Neumaier
Keyword(s):  
Adenosine Receptor ◽  
Molecular Mechanisms ◽  
Animal Species ◽  
Species Differences ◽  
Liver Microsomes ◽  
Suitable Model ◽  
Microsomal Metabolism ◽  
A1 Adenosine Receptor ◽  
Metabolite Profiles

Tracer development for positron emission tomography (PET) requires thorough evaluation of pharmacokinetics, metabolism, and dosimetry of candidate radioligands in preclinical animal studies. Since variations in pharmacokinetics and metabolism of a compound occur in different species, careful selection of a suitable model species is mandatory to obtain valid data. This study focuses on species differences in the in vitro metabolism of three xanthine-derived ligands for the A1 adenosine receptor (A1AR), which, in their 18F-labeled form, can be used to image A1AR via PET. In vitro intrinsic clearance and metabolite profiles of 8-cyclopentyl-3-(3-fluoropropyl)-1-propylxanthine (CPFPX), an established A1AR-ligand, and two novel analogs, 8-cyclobutyl-3-(3-fluoropropyl)-1-propylxanthine (CBX) and 3-(3-fluoropropyl)-8-(1-methylcyclobutyl)-1-propylxanthine (MCBX), were determined in liver microsomes from humans and preclinical animal species. Molecular mechanisms leading to significant differences between human and animal metabolite profiles were also examined. The results revealed significant species differences regarding qualitative and quantitative aspects of microsomal metabolism. None of the tested animal species fully matched human microsomal metabolism of the three A1AR ligands. In conclusion, preclinical evaluation of xanthine-derived A1AR ligands should employ at least two animal species, preferably rodent and dog, to predict in vivo behavior in humans. Surprisingly, rhesus macaques appear unsuitable due to large differences in metabolic activity towards the test compounds.

Metabolism and metabolite profiles in vitro and in vivo of ospemifene in humans and preclinical species

2016 ◽  
Vol 31 (1) ◽  
Author(s):  
Jouko Uusitalo ◽  
Miia Turpeinen ◽  
Ari Tolonen ◽  
Pasi Koskimies ◽  
Risto Lammintausta ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Animal Species ◽  
Active Metabolites ◽  
Receptor Modulator ◽  
Toxicological Studies ◽  
Metabolite Profiles ◽  
Preclinical Species ◽  
Pharmacologically Active

AbstractMetabolite profiles of ospemifene, a novel nonsteroidal selective estrogen receptor modulator, were surveyed as part of its development.The pharmacokinetics of ospemifene and its two major, pharmacologically active metabolites 4-hydroxyospemifene and 4′-hydroxyospemifene, was elucidated in studies of volunteer humans given various doses of ospemifene and in experiments of several animal species (rat, mouse, dog, and cynomolgus monkey), which had been used either for pharmacological or toxicological studies of ospemifene. Metabolites produced inConsiderable interspecies differences were observed in the metabolite profiles and quantities. The major human metabolite, 4-hydroxyospemifene, was produced in substantial amounts bothOverall, there are quantitative and also some qualitative differences in the metabolism of ospemifene in different species. Generally,

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.

Interspecies differences in coagulation profile

2008 ◽  
Vol 100 (09) ◽  
pp. 397-404 ◽  
Author(s):  
Jolanta M. Siller-Matula ◽  
Roberto Plasenzotti ◽  
Alexander Spiel ◽  
Peter Quehenberger ◽  
Bernd Jilma
Keyword(s):  
Animal Models ◽  
Thrombin Generation ◽  
Animal Species ◽  
Species Differences ◽  
Clotting Time ◽  
Coagulation Profile ◽  
Plasma Measurements ◽  
Coagulation And Fibrinolysis ◽  
Maximum Clot Firmness

SummaryMany animals are used in research on blood coagulation and fibrinolysis, but the relevance of animal models to human health is often questioned because of differences between species. The objective was to find an appropriate animal species , which mimics the coagulation profile in humans most adequately. Species differences in the coagulation profile with and without thrombin stimulation in vitro were assessed in whole blood by Rotation Thromboelastometry (ROTEM). Endogenous thrombin generation was measured in platelet-poor plasma. Measurements were performed in blood from five different species: humans, rats, pigs, sheep and rabbits. In humans and sheep, the clotting time (ROTEM) was in the same range with or without thrombin stimulation and a 100-fold lower dose of thrombin (0.002 IU) was required to cause a shortening in the clotting time as compared to rats, pigs and rabbits (0.2 IU) (p<0.05).Similarly, the endogenous thrombin potential (ETP) was in the same range in humans and sheep. The maximum clot firmness with or without thrombin stimulation was similar in rabbits and humans. The maximum lysis with or without thrombin stimulation was similar in humans and pigs. Significant species differences exist in the coagulation profile with or without thrombin stimulation. Most importantly, sheep had a clotting time most similar to humans and could thus be a suitable species for translational coagulation studies. Moreover, our findings confirm the potential usefulness of pigs as an experimental species to study fibrinolytic pathway and support the usefulness of rabbits as a species for examining platelets.

scholarly journals In vitro biotransformation of pyrrolizidine alkaloids in different species: part II—identification and quantitative assessment of the metabolite profile of six structurally different pyrrolizidine alkaloids

2020 ◽  
Vol 94 (11) ◽  
pp. 3759-3774
Author(s):  
Ina Geburek ◽  
Dieter Schrenk ◽  
Anja These
Keyword(s):  
Human Liver ◽  
Pyrrolizidine Alkaloids ◽  
High Resolution Mass Spectrometry ◽  
Liver Microsomes ◽  
Metabolite Profile ◽  
Human Liver Microsomes ◽  
Rat Liver Microsomes ◽  
Metabolite Profiles ◽  
Fragmentation Patterns

Abstract Pyrrolizidine alkaloids (PA) exert their toxic effects only after bioactivation. Although their toxicity has already been studied and metabolic pathways including important metabolites were described, the quantification of the latter revealed a large unknown portion of the metabolized PA. In this study, the qualitative and quantitative metabolite profiles of structurally different PAs in rat and human liver microsomes were investigated. Between five metabolites for europine and up to 48 metabolites for lasiocarpine were detected. Proposals for the chemical structure of each metabolite were derived based on fragmentation patterns using high-resolution mass spectrometry. The metabolite profiles of the diester PAs showed a relatively good agreement between both species. The metabolic reactions were summarized into three groups: dehydrogenation, oxygenation, and shortening of necic acid(s). While dehydrogenation of the necine base is considered as bioactivation, both other routes are considered as detoxification steps. The most abundant changes found for open chained diesters were dealkylations, while the major metabolic pathway for cyclic diesters was oxygenation especially at the nitrogen atom. In addition, all diester PAs formed several dehydrogenation products, via the insertion of a second double bond in the necine base, including the formation of glutathione conjugates. In rat liver microsomes, all investigated PAs formed dehydropyrrolizidine metabolites with the highest amount formed by lasiocarpine, whereas in human liver microsomes, these metabolites could only be detected for diesters. Our findings demonstrate that an extensive analysis of PA metabolism can provide the basis for a better understanding of PA toxicity and support future risk assessment.

scholarly journals Large species differences in the pattern of snPI RNA which can distinguish ape from human.

1979 ◽  
Vol 80 (3) ◽  
pp. 778-783 ◽  
Author(s):  
B J Benecke ◽  
S Penman
Keyword(s):  
Animal Species ◽  
Species Differences ◽  
Cell Types ◽  
Large Species ◽  
Closely Related Species ◽  
Precursor Rna ◽  
Polymerase I ◽  
Ribosomal Precursor ◽  
Different Cell Types

The snPI RNA species are a recently described set of molecules whose sizes range from 5S to 10S. They can be labeled in vitro in isolated nuclei and are apparently formed by an RNA polymerase I type of activity. However, in contrast to ribosomal precursor RNA, the usual polymerase I product, they are not found in the nucleolus but rather are located in the nucleoplasm. The snPI RNAs have been found in all mammalian cell types studied. The spectrum seen in gel electrophoresis is unique to each animal species studied but is essentially the same in different cell types within a species. The differences in snPI patterns are quite large between even closely related species and are clearly distinguishable in gorilla and human cells.

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