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Book ; Online: A dictionary and grammatical sketch of Dagaare (Volume 4)

Ali, Mark / Grimm, Scott / Bodomo, Adams

2021

Keywords	linguistics ; Language Arts & Disciplines ; Linguistics
Size	1 Online-Ressource
Publisher	Language Science Press
Document type	Book ; Online
Note	English ; Open Access
HBZ-ID	HT021048712
Database	ZB MED Catalogue: Medicine, Health, Nutrition, Environment, Agriculture

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Article ; Online: Predictability of meaning in grammatical encoding: Optional plural marking.

Kurumada, Chigusa / Grimm, Scott

Cognition

2019 Volume 191, Page(s) 103953

Abstract: The markedness principle plays a central role in linguistic theory: marked grammatical categories (like plural) tend to receive more linguistic encoding (e.g., morphological marking), while unmarked categories (like singular) tend to receive less ... ...

Abstract	The markedness principle plays a central role in linguistic theory: marked grammatical categories (like plural) tend to receive more linguistic encoding (e.g., morphological marking), while unmarked categories (like singular) tend to receive less linguistic encoding. What precisely makes a grammatical category or meaning marked, however, remains unclear. One prominent proposal attributes markedness to the frequency or predictability of meanings: infrequent or less predictable meanings are more likely to receive extra linguistic encoding than frequent or more predictable meanings. Existing support for the predictability account is limited to correlational evidence, leaving open whether meaning predictability can cause markedness patterns. We present two miniature language learning experiments that directly assess effects of predictability on morphological plural marking. We find that learners preferentially produce plural marking on nouns that are less probable to occur with plural meaning-despite the fact that no such pattern was present in learners' input. This suggests that meaning predictability can cause the markedness patterns like those that are cross-linguistically observed.
MeSH term(s)	Adult ; Humans ; Probability Learning ; Psycholinguistics
Language	English
Publishing date	2019-06-24
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1499940-7
ISSN	1873-7838 ; 0010-0277
ISSN (online)	1873-7838
ISSN	0010-0277
DOI	10.1016/j.cognition.2019.04.022
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Article ; Online: Deep Artificial Neural Networks Reveal a Distributed Cortical Network Encoding Propositional Sentence-Level Meaning.

Anderson, Andrew James / Kiela, Douwe / Binder, Jeffrey R / Fernandino, Leonardo / Humphries, Colin J / Conant, Lisa L / Raizada, Rajeev D S / Grimm, Scott / Lalor, Edmund C

The Journal of neuroscience : the official journal of the Society for Neuroscience

2021 Volume 41, Issue 18, Page(s) 4100–4119

Abstract: Understanding how and where in the brain sentence-level meaning is constructed from words presents a major scientific challenge. Recent advances have begun to explain brain activation elicited by sentences using vector models of word meaning derived from ...

Abstract	Understanding how and where in the brain sentence-level meaning is constructed from words presents a major scientific challenge. Recent advances have begun to explain brain activation elicited by sentences using vector models of word meaning derived from patterns of word co-occurrence in text corpora. These studies have helped map out semantic representation across a distributed brain network spanning temporal, parietal, and frontal cortex. However, it remains unclear whether activation patterns within regions reflect unified representations of sentence-level meaning, as opposed to superpositions of context-independent component words. This is because models have typically represented sentences as "bags-of-words" that neglect sentence-level structure. To address this issue, we interrogated fMRI activation elicited as 240 sentences were read by 14 participants (9 female, 5 male), using sentences encoded by a recurrent deep artificial neural-network trained on a sentence inference task (InferSent). Recurrent connections and nonlinear filters enable InferSent to transform sequences of word vectors into unified "propositional" sentence representations suitable for evaluating intersentence entailment relations. Using voxelwise encoding modeling, we demonstrate that InferSent predicts elements of fMRI activation that cannot be predicted by bag-of-words models and sentence models using grammatical rules to assemble word vectors. This effect occurs throughout a distributed network, which suggests that propositional sentence-level meaning is represented within and across multiple cortical regions rather than at any single site. In follow-up analyses, we place results in the context of other deep network approaches (ELMo and BERT) and estimate the degree of unpredicted neural signal using an "experiential" semantic model and cross-participant encoding.
MeSH term(s)	Adult ; Cerebral Cortex/diagnostic imaging ; Cerebral Cortex/physiology ; Comprehension/physiology ; Computer Simulation ; Female ; Humans ; Language ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Neural Networks, Computer ; Reading ; Semantics ; Young Adult
Language	English
Publishing date	2021-03-22
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	604637-x
ISSN	1529-2401 ; 0270-6474
ISSN (online)	1529-2401
ISSN	0270-6474
DOI	10.1523/JNEUROSCI.1152-20.2021
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Article ; Online: Pharmacokinetics, metabolism and excretion of [(14)C]-lanicemine (AZD6765), a novel low-trapping N-methyl-d-aspartic acid receptor channel blocker, in healthy subjects.

Guo, Jian / Zhou, Diansong / Grimm, Scott W / Bui, Khanh H

Xenobiotica; the fate of foreign compounds in biological systems

2015 Volume 45, Issue 3, Page(s) 244–255

Abstract: 1.(1S)-1-phenyl-2-(pyridin-2-yl)ethanamine (lanicemine; AZD6765) is a low-trapping N-methyl-d-aspartate (NMDA) channel blocker that has been studied as an adjunctive treatment in major depressive disorder. The metabolism and disposition of lanicemine was ...

Abstract	1.(1S)-1-phenyl-2-(pyridin-2-yl)ethanamine (lanicemine; AZD6765) is a low-trapping N-methyl-d-aspartate (NMDA) channel blocker that has been studied as an adjunctive treatment in major depressive disorder. The metabolism and disposition of lanicemine was determined in six healthy male subjects after a single intravenous infusion dose of 150 mg [(14)C]-lanicemine. 2.Blood, urine and feces were collected from all subjects. The ratios of Cmax and AUC(0-∞) of lanicemine to plasma total radioactivity were 84 and 66%, respectively, indicating that lanicemine was the major circulating component with T1/2 at 16 h. The plasma clearance of lanicemine was 8.3 L/h, revealing that lanicemine is a low-clearance compound. The mean recovery of radioactivity from urine was 93.8% of radioactive dose. 3.In urine samples, 10 metabolites of lanicemine were identified. Among which, an O-glucuronide conjugate (M1) was the most abundant metabolite (∼11% of the dose in excreta). In plasma, the circulatory metabolites were identified as a para-hydroxylated metabolite (M1), an O-glucuronide (M2), an N-carbamoyl glucuronide (M3) and an N-acetylated metabolite (M6). The average amount of each of metabolite was less than 4% of total radioactivity detected in plasma or urine. 4.In conclusion, lanicemine is a low-clearance compound. The unchanged drug and metabolites are predominantly eliminated via urinary excretion.
MeSH term(s)	Administration, Intravenous ; Adult ; Carbon Radioisotopes ; Feces/chemistry ; Healthy Volunteers ; Humans ; Male ; Mass Spectrometry ; Metabolome ; Middle Aged ; Phenethylamines/analysis ; Phenethylamines/chemistry ; Phenethylamines/metabolism ; Phenethylamines/pharmacokinetics ; Pyridines/analysis ; Pyridines/chemistry ; Pyridines/metabolism ; Pyridines/pharmacokinetics ; Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors ; Receptors, N-Methyl-D-Aspartate/metabolism ; Time Factors
Chemical Substances	AZD6765 ; Carbon Radioisotopes ; Phenethylamines ; Pyridines ; Receptors, N-Methyl-D-Aspartate
Language	English
Publishing date	2015-03
Publishing country	England
Document type	Clinical Trial, Phase I ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	120287-x
ISSN	1366-5928 ; 0049-8254
ISSN (online)	1366-5928
ISSN	0049-8254
DOI	10.3109/00498254.2014.966175
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Article ; Online: Fusidic Acid Inhibits Hepatic Transporters and Metabolic Enzymes: Potential Cause of Clinical Drug-Drug Interaction Observed with Statin Coadministration.

Gupta, Anshul / Harris, Jennifer J / Lin, Jianrong / Bulgarelli, James P / Birmingham, Bruce K / Grimm, Scott W

Antimicrobial agents and chemotherapy

2016 Volume 60, Issue 10, Page(s) 5986–5994

Abstract: Fusidic acid (FA), which was approved in the 1960s in many European and Asian countries, has gained renewed interest due to its continued effectiveness against methicillin-resistant Staphylococcus aureus As rhabdomyolysis has been reported upon ... ...

Abstract	Fusidic acid (FA), which was approved in the 1960s in many European and Asian countries, has gained renewed interest due to its continued effectiveness against methicillin-resistant Staphylococcus aureus As rhabdomyolysis has been reported upon coadministration of FA with statins, we aimed to elucidate the underlying molecular mechanisms that contribute to FA-statin drug-drug interactions. Because of the association between rhabdomyolysis and increased exposure to statins, we investigated if cytochrome P450 (CYP) enzymes and transporters involved in the disposition of various statins are inhibited by FA. FA was found to inhibit BCRP and OATP1B1 but not P-gp. In overexpressing cell systems, FA inhibited BCRP-mediated efflux (50% inhibitory concentration [IC50], ∼50 to 110 μM) and OATP1B1-mediated uptake (IC50, ∼4 to 35 μM) of statins at clinically relevant concentrations achievable in the intestine and liver (based on a 550-mg oral dose of FA, the expected maximum theoretical gastrointestinal concentration is ∼4 mM, and the maximum total or unbound concentration in the inlet to the liver was reported to be up to 223 μM or 11 μM, respectively, upon multiple dosing). Similarly, FA inhibited metabolism of statins in human liver microsomes (IC50, ∼17 to 195 μM). These data suggest that FA inhibits at least 3 major dispositional pathways (BCRP, OATP1B1, and CYP3A) and thus affects the clearance of several statins. We confirmed that FA is eliminated via phase 1 metabolism (primarily via CYP3A); however, there is also some phase 2 metabolism (mediated primarily by UGT1A1). Taken together, these data provide evidence for molecular mechanisms that may explain the occurrence of rhabdomyolysis when FA is administered with statins.
MeSH term(s)	ATP Binding Cassette Transporter, Sub-Family G, Member 2/antagonists & inhibitors ; ATP Binding Cassette Transporter, Sub-Family G, Member 2/genetics ; ATP Binding Cassette Transporter, Sub-Family G, Member 2/metabolism ; ATP-Binding Cassette, Sub-Family B, Member 1/genetics ; ATP-Binding Cassette, Sub-Family B, Member 1/metabolism ; Animals ; Anti-Bacterial Agents/pharmacology ; Cytochrome P-450 CYP3A/genetics ; Cytochrome P-450 CYP3A/metabolism ; Cytochrome P-450 Enzyme Inhibitors/pharmacology ; Dogs ; Drug Combinations ; Drug Interactions ; Fusidic Acid/pharmacology ; Gene Expression ; HEK293 Cells ; Hepatocytes/drug effects ; Hepatocytes/metabolism ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology ; Inactivation, Metabolic/drug effects ; Inhibitory Concentration 50 ; Madin Darby Canine Kidney Cells ; Microsomes, Liver/drug effects ; Microsomes, Liver/metabolism ; Neoplasm Proteins/antagonists & inhibitors ; Neoplasm Proteins/genetics ; Neoplasm Proteins/metabolism ; Primary Cell Culture ; Solute Carrier Organic Anion Transporter Family Member 1b1/antagonists & inhibitors ; Solute Carrier Organic Anion Transporter Family Member 1b1/genetics ; Solute Carrier Organic Anion Transporter Family Member 1b1/metabolism
Chemical Substances	ABCG2 protein, human ; ATP Binding Cassette Transporter, Sub-Family G, Member 2 ; ATP-Binding Cassette, Sub-Family B, Member 1 ; Anti-Bacterial Agents ; Cytochrome P-450 Enzyme Inhibitors ; Drug Combinations ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; Neoplasm Proteins ; SLCO1B1 protein, human ; Solute Carrier Organic Anion Transporter Family Member 1b1 ; Fusidic Acid (59XE10C19C) ; CYP3A protein, human (EC 1.14.14.1) ; Cytochrome P-450 CYP3A (EC 1.14.14.1)
Language	English
Publishing date	2016-10
Publishing country	United States
Document type	Journal Article
ZDB-ID	217602-6
ISSN	1098-6596 ; 0066-4804
ISSN (online)	1098-6596
ISSN	0066-4804
DOI	10.1128/AAC.01335-16
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Zs.A 809: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Absorption, distribution, metabolism and elimination of 14C-ETX0914, a novel inhibitor of bacterial type-II topoisomerases in rodents.

Guo, Jian / Joubran, Camil / Luzietti, Ricardo A / Basarab, Gregory S / Grimm, Scott W / Vishwanathan, Karthick

Xenobiotica; the fate of foreign compounds in biological systems

2016 Volume 47, Issue 1, Page(s) 31–49

Abstract: 1. ETX0914 is a novel bacterial topoisomerase inhibitor that has a novel mode-of-inhibition and is in clinical development for the treatment of infections caused by Neisseria gonorrhoeae. 2. The in vitro biotransformation studies of ETX0914 using mouse, ... ...

Abstract	1. ETX0914 is a novel bacterial topoisomerase inhibitor that has a novel mode-of-inhibition and is in clinical development for the treatment of infections caused by Neisseria gonorrhoeae. 2. The in vitro biotransformation studies of ETX0914 using mouse, rat, dog and human hepatocytes showed moderate intrinsic clearance in mouse and rat and low intrinsic clearance in dog and human. 3. Following intravenous administration of [
MeSH term(s)	Animals ; Barbiturates/pharmacokinetics ; DNA Topoisomerases, Type II/metabolism ; Dogs ; Humans ; Mice ; Rats ; Spiro Compounds/pharmacokinetics ; Topoisomerase Inhibitors/pharmacokinetics
Chemical Substances	Barbiturates ; Spiro Compounds ; Topoisomerase Inhibitors ; DNA Topoisomerases, Type II (EC 5.99.1.3) ; zoliflodacin (FWL2263R77)
Language	English
Publishing date	2016-04-28
Publishing country	England
Document type	Journal Article
ZDB-ID	120287-x
ISSN	1366-5928 ; 0049-8254
ISSN (online)	1366-5928
ISSN	0049-8254
DOI	10.3109/00498254.2016.1156186
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Article: Liquid chromatography–tandem mass spectrometry method for measurement of nicotine N-glucuronide: A marker for human UGT2B10 inhibition

Guo, Jian / Zhou, Diansong / Grimm, Scott W

Journal of pharmaceutical and biomedical analysis. 2011 July 15, v. 55, no. 5

2011

Abstract: Nicotine is considered to be a specific substrate for UGT2B10, an isoform of human uridine diphosphate glucuronosyltransferase (UGT). In the present study, a sensitive and selective liquid chromatography/tandem mass spectrometry (LC–MS–MS) method for ... ...

Abstract	Nicotine is considered to be a specific substrate for UGT2B10, an isoform of human uridine diphosphate glucuronosyltransferase (UGT). In the present study, a sensitive and selective liquid chromatography/tandem mass spectrometry (LC–MS–MS) method for quantification of nicotine N-glucuronide in pooled human liver microsomal incubates was developed and validated. Proteins in a 200μL aliquot of incubation solution were precipitated by adding 40μL 35% perchloric acid. The overall extraction efficiency was greater than 98%. Nicotine N-glucuronide and internal standard were recorded using selected reaction monitoring in positive ion electrospray with ion transitions of m/z 339–163 and m/z 342–166, respectively. The linear calibration curve was obtained over the concentration range of 10–1000nM, with a lower limit of quantification of 10nM. The intra-day and inter-day precision (% CV) and accuracy (% bias) of the method were within 15% at all quality control levels. Nicotine glucuronide in processed samples was stable for 24h at room temperature and 48h at 4°C based on the stability experiments performed in this study. This established method was employed to evaluate the inhibitory effects of five target compounds including amitriptyline, hecogenin, imipramine, lamotrigine, and trifluoperazine on enzymatic activity of UGT2B10. IC₅₀ values for inhibition of nicotine N-glucuronidation by amitriptyline, imipramine, lamotrigine, and trifluoperazine were calculated. Trifluoperazine was found to be a non-substrate inhibitor for human UGT2B10.
Keywords	enzyme activity ; humans ; inhibitory concentration 50 ; liquid chromatography ; liver ; monitoring ; nicotine ; perchloric acid ; proteins ; quality control ; tandem mass spectrometry ; temperature ; trifluoperazine ; uridine diphosphate
Language	English
Dates of publication	2011-0715
Size	p. 964-971.
Publishing place	Elsevier B.V.
Document type	Article
ZDB-ID	604917-5
ISSN	0731-7085
ISSN	0731-7085
DOI	10.1016/j.jpba.2011.03.034
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Liquid chromatography-tandem mass spectrometry method for measurement of nicotine N-glucuronide: a marker for human UGT2B10 inhibition.

Guo, Jian / Zhou, Diansong / Grimm, Scott W

Journal of pharmaceutical and biomedical analysis

2011 Volume 55, Issue 5, Page(s) 964–971

Abstract	Nicotine is considered to be a specific substrate for UGT2B10, an isoform of human uridine diphosphate glucuronosyltransferase (UGT). In the present study, a sensitive and selective liquid chromatography/tandem mass spectrometry (LC-MS-MS) method for quantification of nicotine N-glucuronide in pooled human liver microsomal incubates was developed and validated. Proteins in a 200μL aliquot of incubation solution were precipitated by adding 40μL 35% perchloric acid. The overall extraction efficiency was greater than 98%. Nicotine N-glucuronide and internal standard were recorded using selected reaction monitoring in positive ion electrospray with ion transitions of m/z 339-163 and m/z 342-166, respectively. The linear calibration curve was obtained over the concentration range of 10-1000nM, with a lower limit of quantification of 10nM. The intra-day and inter-day precision (% CV) and accuracy (% bias) of the method were within 15% at all quality control levels. Nicotine glucuronide in processed samples was stable for 24h at room temperature and 48h at 4°C based on the stability experiments performed in this study. This established method was employed to evaluate the inhibitory effects of five target compounds including amitriptyline, hecogenin, imipramine, lamotrigine, and trifluoperazine on enzymatic activity of UGT2B10. IC(50) values for inhibition of nicotine N-glucuronidation by amitriptyline, imipramine, lamotrigine, and trifluoperazine were calculated. Trifluoperazine was found to be a non-substrate inhibitor for human UGT2B10.
MeSH term(s)	Amitriptyline/analysis ; Calibration ; Chromatography, Liquid/methods ; Dose-Response Relationship, Drug ; Drug Evaluation, Preclinical/methods ; Glucuronates/analysis ; Glucuronosyltransferase/antagonists & inhibitors ; Humans ; Imipramine/analysis ; Inhibitory Concentration 50 ; Kinetics ; Microsomes, Liver/drug effects ; Nicotine/analogs & derivatives ; Nicotine/analysis ; Nicotine/chemistry ; Reproducibility of Results ; Spectrometry, Mass, Electrospray Ionization/methods ; Tandem Mass Spectrometry/methods ; Temperature ; Trifluoperazine/analysis
Chemical Substances	Glucuronates ; nicotine N-glucuronide (152306-59-7) ; Amitriptyline (1806D8D52K) ; Trifluoperazine (214IZI85K3) ; Nicotine (6M3C89ZY6R) ; UGT2B10 protein, human (EC 2.4.1.-) ; Glucuronosyltransferase (EC 2.4.1.17) ; Imipramine (OGG85SX4E4)
Language	English
Publishing date	2011-07-15
Publishing country	England
Document type	Journal Article
ZDB-ID	604917-5
ISSN	1873-264X ; 0731-7085
ISSN (online)	1873-264X
ISSN	0731-7085
DOI	10.1016/j.jpba.2011.03.034
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Article ; Online: In vitro evaluation of potential drug-drug interactions with ticagrelor: cytochrome P450 reaction phenotyping, inhibition, induction, and differential kinetics.

Zhou, Diansong / Andersson, Tommy B / Grimm, Scott W

Drug metabolism and disposition: the biological fate of chemicals

2011 Volume 39, Issue 4, Page(s) 703–710

Abstract: Ticagrelor is an orally administered, antiplatelet agent that inhibits the prothrombotic effects of ADP on the platelet by antagonizing the P2Y(12) receptor. Ticagrelor is a reversibly binding direct-acting P2Y(12) antagonist and does not require ... ...

Abstract	Ticagrelor is an orally administered, antiplatelet agent that inhibits the prothrombotic effects of ADP on the platelet by antagonizing the P2Y(12) receptor. Ticagrelor is a reversibly binding direct-acting P2Y(12) antagonist and does not require metabolic activation to achieve its antiplatelet effect. CYP3A4 and CYP3A5 appear to be the enzymes predominantly responsible for the formation of the ticagrelor active and inactive metabolites, AR-C124910XX and AR-C133913XX. The apparent K(m) values in human liver microsomes are 27.0 and 38.8 μM, with V(max) values of 730 and 417 pmol/min/mg for AR-C124910XX and AR-C133913XX, respectively. Ticagrelor moderately inhibited CYP2C9 activity in human liver microsomes with an IC(50) of 10.5 μM, while exhibiting little or no inhibition of CYP1A2, CYP2B6, CYP2C8, CYP2C19, CYP2D6, and CYP2E1. In human liver microsomes, ticagrelor inhibited midazolam 4-hydroxylation with an IC(50) of 8.2 μM, while activating 1'-hydroxylation of midazolam. Studies with recombinant enzymes suggested that cytochrome b(5) and CYP3A4 interactions play a significant role in this differential kinetic behavior. Evaluated in fresh human hepatocytes at concentration up to 20 μM, ticagrelor was not an inducer of CYP1A2 or CYP3A4. Although ticagrelor exhibited a tendency for CYP2B6 and CYP2C9 induction, its potential to cause drug interactions via the induction of these enzymes is low when its exposure at a therapeutic dose is considered.
MeSH term(s)	Adenosine/analogs & derivatives ; Adenosine/chemistry ; Adenosine/metabolism ; Adenosine/pharmacokinetics ; Adjuvants, Anesthesia/metabolism ; Cytochrome P-450 Enzyme Inhibitors ; Cytochrome P-450 Enzyme System/metabolism ; Drug Interactions ; Hepatocytes/drug effects ; Hepatocytes/metabolism ; Humans ; Microsomes, Liver/drug effects ; Microsomes, Liver/metabolism ; Midazolam/metabolism ; Platelet Aggregation Inhibitors/chemistry ; Platelet Aggregation Inhibitors/metabolism ; Platelet Aggregation Inhibitors/pharmacokinetics ; Purinergic P2Y Receptor Antagonists/chemistry ; Purinergic P2Y Receptor Antagonists/metabolism ; Purinergic P2Y Receptor Antagonists/pharmacokinetics
Chemical Substances	Adjuvants, Anesthesia ; Cytochrome P-450 Enzyme Inhibitors ; Platelet Aggregation Inhibitors ; Purinergic P2Y Receptor Antagonists ; Cytochrome P-450 Enzyme System (9035-51-2) ; Ticagrelor (GLH0314RVC) ; Adenosine (K72T3FS567) ; Midazolam (R60L0SM5BC)
Language	English
Publishing date	2011-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	186795-7
ISSN	1521-009X ; 0090-9556
ISSN (online)	1521-009X
ISSN	0090-9556
DOI	10.1124/dmd.110.037143
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Article ; Online: Disposition and metabolism of ticagrelor, a novel P2Y12 receptor antagonist, in mice, rats, and marmosets.

Li, Yan / Landqvist, Claire / Grimm, Scott W

Drug metabolism and disposition: the biological fate of chemicals

2011 Volume 39, Issue 9, Page(s) 1555–1567

Abstract: Ticagrelor is a reversibly binding and selective oral P2Y(12) antagonist, developed for the prevention of atherothrombotic events in patients with acute coronary syndromes. The disposition and metabolism of [(14)C]ticagrelor was investigated in mice, ... ...

Abstract	Ticagrelor is a reversibly binding and selective oral P2Y(12) antagonist, developed for the prevention of atherothrombotic events in patients with acute coronary syndromes. The disposition and metabolism of [(14)C]ticagrelor was investigated in mice, rats, and marmosets to demonstrate that these preclinical toxicity species showed similar metabolic profiles to human. Incubations with hepatocytes or microsomes from multiple species were also studied to compare with in vivo metabolic profiles. The routes of excretion were similar for both oral and intravenous administration in mice, rats, and marmosets with fecal excretion being the major elimination pathway accounting for 59 to 96% of the total radioactivity administered. Urinary excretion of drug-related material accounted for only 1 to 15% of the total radioactivity administered. Milk samples from lactating rats displayed significantly higher levels of total radioactivity than plasma after oral administration of ticagrelor. This demonstrated that ticagrelor and/or its metabolites were readily transferred into rat milk and that neonatal rats could be exposed to ticagrelor-related compounds via maternal milk. Ticagrelor and active metabolite AR-C124910 (loss of hydroxyethyl side chain) were the major components in plasma from all species studied and similar to human plasma profiles. The primary metabolite of ticagrelor excreted in urine across all species was an inactive metabolite, AR-C133913 (loss of difluorophenylcyclopropyl group). Ticagrelor, AR-C124910, and AR-C133913 were the major components found in feces from the three species examined. Overall, in vivo metabolite profiles were qualitatively similar across all species and consistent with in vitro results.
MeSH term(s)	Adenosine/analogs & derivatives ; Adenosine/blood ; Adenosine/metabolism ; Adenosine/pharmacokinetics ; Adenosine/urine ; Administration, Oral ; Animals ; Callithrix ; Dogs ; Feces ; Female ; Hepatocytes/metabolism ; Humans ; Inactivation, Metabolic ; Injections, Intravenous ; Male ; Mice ; Microsomes, Liver/metabolism ; Milk/metabolism ; Purinergic P2Y Receptor Antagonists/blood ; Purinergic P2Y Receptor Antagonists/metabolism ; Purinergic P2Y Receptor Antagonists/urine ; Rats ; Rats, Sprague-Dawley
Chemical Substances	Purinergic P2Y Receptor Antagonists ; Ticagrelor (GLH0314RVC) ; Adenosine (K72T3FS567)
Language	English
Publishing date	2011-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	186795-7
ISSN	1521-009X ; 0090-9556
ISSN (online)	1521-009X
ISSN	0090-9556
DOI	10.1124/dmd.111.039669
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