bluuebunny/crossref_metadata_2025 huggingface dataset:
Seizing an Opportunity for the Endocannabinoid System
Authors: Alger Bradley E.
Published: October 2014

Exogenous cannabinoids can limit seizures and neurodegeneration, and their actions are largely mimicked by endogenous cannabinoids (endocannabinoids). Endocannabinoids are mobilized by epileptiform activity and in turn influence this activity by inhibiting synaptic transmission; both excitatory and some inhibitory synapses can be suppressed, leading to potentially complex outcomes. Moreover, the endocannabinoid system is not a fixed entity, and its strength can be enhanced or reduced. Endocannabinoids and their receptors are altered by epileptic seizures in ways that can reduce the efficacy of both exogenous and endogenous cannabinoids in sometimes unexpected ways.
Massification in Higher Education Institutions in Africa: Causes, Consequences and Responses
Authors: Mohamedbhai Goolam
Published: October 2014

Most public higher education institutions in Africa, in response to historical conditions, have enrolled students in excess of their capacity, resulting in massification and negative consequences on educational quality. Increased enrolment has addressed issues of equity; but the equally important issue of ensuring equity in success for the enrolled students has received limited attention. Apparently graduation rates in higher education in Africa remain fairly low. Higher education institutions have taken several corrective measures to address the consequences of massification. Governments have also created new institutions and put quality assurance systems in place. There have also been continental responses. Sub-Saharan Africa has the lowest tertiary enrolment of any world region, a handicap in its development. It must also meet the demands of its rapidly increasing secondary school graduates. There is a compelling need to further increase tertiary enrolment, a situation that challenges both institutions and countries. The growth in private higher education, if regulated and quality-controlled, could relieve this pressure.  Pour des raisons historiques, la majorité des établissements d’enseignement supérieur d’Afrique admet plus d’étudiants qu’elle ne peut en accueillir. Ceci conduit à la massification de l’enseignement supérieur et a des conséquences négatives sur sa qualité. L’augmentation de la participation a permis de répondre à des problèmes d’équité, mais la tout aussi importante question de l’équité dans la réussite des étudiants admis a reçu une attention limitée. Le taux de réussite dans l’enseignement supérieur en Afrique reste faible. Les établissements d’enseignement supérieur ont mis en place plusieurs mesures visant à corriger les conséquences néfastes de la massification. Les gouvernements ont aussi créé de nouvelles institutions et mis en place des systèmes d’assurance qualité. Des réponses ont par ailleurs été proposées à l’échelle du continent. Cependant, l’Afrique sub-saharienne a le plus faible taux d’inscription dans l’enseignement supérieur du monde, un handicap pour son développement. Elle doit aussi répondre aux demandes d’une population de diplômés du secondaire qui augmente rapidement. Il est impossible de nier la nécessité d’augmenter les admissions dans l’enseignement supérieur, une situation qui pose des problèmes aussi bien aux établissements qu’aux nations. La croissance des établissements privés pourrait permettre de relâcher la pression, s’ils sont correctement régulés et contrôlés en termes de qualité.
No, You Wouldn’t Want to Not Read this Paper: a working paper on a typology of negation across the romance languages
Authors: Fleming Bryan , Belko Danielle , Nagengast Jeffrey
Published: October 2014

In this paper, we discuss negation in several languages of the same family—languages which are strikingly similar in many aspects but which use varying strategies to form negatives. We begin our discussion by describing Rafaella Zanuttini's investigation into the typology of Romance languages in terms of how negation is formed. We follow with a more detailed description of negation strategies in several widely spoken romance languages, viz., Spanish, Italian, and French—bringing in information from other dialects when useful or interesting. Next, we attempt to discuss Zanuttini's typology vis-à-vis the corpora of data we have in the aforementioned languages, citing the (in)compatibility/(non-)compliance of these languages with her typological descriptions. Lastly, we discuss some historical insight into why these differences exist and follow that with descriptions of languages and dialects not referenced in Zanuttini's article. We also discuss any trends that these languages exhibit in relation to Zanuttini's generalizations.
On the Psycholinguistic Activation of Idioms’ Parts
Authors: Short Brandon
Published: October 2014

This article examines the psycholinguistic "activation" of idioms and their constituent parts. It considers whether idioms are activated as units or whether and to what extent they psycholinguistically "activate" or "prime" the mental lexical entries for each individual word within the individual. This is an imporatant question because the unique characteristic of idioms that often, the meaning of the idiom taken as a synthetic whole has little or nothing to do with the meanings of its ingredient parts.
Etymology of Quechua Kay
Authors: Geary Jonathan
Published: October 2014

This article examines the Quechua word kay, which is often glossed as 'this' and treated as a demonstrative pronoun.  As I propose in this paper, kay actually consists of the verb stem ka- 'to be, exist' and the substantivizing suffix -y, having a meaning closer to 'existence' in all circumstances.
La Cour africaine des droits de l’homme et des peuples ou le miroir stendhalien du système africain de protection des droits de l’homme
Authors: Diop Abdou-Khadre
Published: October 2014

La Cour africaine des droits de l’homme et des peuples (ci-après denommée Cour africaine) est la plus jeune juridiction continentale de protection des droits de l’homme. Elle est aussi celle qui aura l’espérance de vie la plus courte, car, avant même sa naissance, sa mort prochaine est annoncée avec le Protocole de Sharm El Sheik qui prévoit la fusion de la Cour africaine des droits de l’homme avec la Cour de justice de l’Union africaine en une Cour africaine de justice et des droits de l’homme. Installée le 2 juillet 2006, et bien qu’elle soit promise à un avenir très incertain, la Cour africaine des droits de l’homme et des peuples n’en mérite pas moins de faire l’objet d’un investissement scientifique. Elle est en effet le premier organe judiciaire créé à l’échelle du continent africain (qui, en outre, servira de base à la future Cour africaine de justice et des droits de l’homme) et est établie dans le sillage d’une demi-douzaine de cours sous-régionales, ce qui laisse un décor à la fois complexe et original.
The hydrogeological well database TANGRAM©: a tool for data processing to support groundwater assessment
Authors: Bonomi Tullia , Fumagalli Letizia , Rotiroti Marco , Bellani Alberto , Cavallin Angelo
Published: October 2014

At the Department of Earth and Environmental Sciences of the University of Milano-Bicocca (DISAT-UNIMIB), a hydrogeological well database, called TANGRAM©, has been developed and published on line at www.TANGRAM.samit.unimib.it, developing an earlier 1989 DOS version. This package can be used to store, display, and process all data related to water wells, including administrative information, well characteristics, stratigraphic logs, water levels, pumping rates, and other hydrogeological information. Currently, the database contains more than 39.200 wells located in the Italian region of Lombardy (90%), Piedmont (9%) and Valle d’Aosta (1%). TANGRAM© has been created both as a tool for researches and for public administration’s administrators who have projects in common with DISAT-UNIMIB. Indeed, transferring wells data from paper into TANGRAM© offers both an easier and more robust way to correlate hydrogeological data and a more organized management of the administrative information. Some Administrations use TANGRAM© regularly as a tool for wells data management (Brescia Province, ARPA Valle Aosta). An innovative aspect of the database is the quantitative extraction of stratigraphic data. In the part of the software intended for research purposes, all well logs are translated into 8-digit alphanumeric codes and the user composes the code interpreting the description at each stratigraphic level. So the stratigraphic well data can be coded, then quantified and processed. This is made possible by attributing a weight to the digits of the code for textures. The program calculates the weighted percentage of the chosen lithology, as related to each individual layer. These extractions are the starting point for subsequent hydrogeological studies: well head protection area, reconstruction of the dynamics of flow, realization of the quarry plans and flux and transport hydrogeological models. The results of a two-dimensional distribution of coarse, medium and fine sized material in the first 80 meters of depth are presented here for a study area located within the Province of Brescia (Italy).
Demonstrating managed aquifer recharge as a solution for climate change adaptation: results from Gabardine project and asemwaterNet coordination action in the Algarve region (Portugal)
Authors: Lobo Ferreira João Paulo , Leitão Teresa E.
Published: October 2014

In the Algarve southern Portugal region, Managed Aquifer Recharge (MAR) research activities have been developed to provide not only water surplus storage in aquifers during wet years, focusing in the Querença-Silves aquifer (FP6 ASEMWATERNet Coordination Action), but also groundwater quality rehabilitation in the Campina de Faro aquifer (FP6 Gabardine Project). Following MAR research potentialities in southern Portugal, this paper describes the objectives, conceptual demonstration, background and capabilities of one of the selected Circum-Mediterranean pilot sites (in Portugal) that will be researched in the new FP7-ENV-2013-WATER-INNO-DEMO MARSOL project, which started Dec. 1st, 2013. In the Algarve pilot site, several case-study areas will be located in the Querença-Silves aquifer and in the Campina de Faro aquifer.
Next‐Gen Sequencing‐Based Mapping and Identification of Ethyl Methanesulfonate‐Induced Mutations in Arabidopsis thaliana
Authors: Zhang Xue‐Cheng , Millet Yves , Ausubel Frederick M. , Borowsky Mark
Published: October 2014

Forward genetic analysis using ethyl methanesulfonate (EMS) mutagenesis has proven to be a powerful tool in biological research, but identification and cloning of causal mutations by conventional genetic mapping approaches is a painstaking process. Recent advances in next‐gen sequencing have greatly invigorated the process of identifying EMS‐induced mutations corresponding to a specific phenotype in model genetic hosts, including the plant Arabidopsis thaliana and the nematode Caenorhabditis elegans. Next‐gen sequencing of bulked F2 mutant recombinants produces a wealth of high‐resolution genetic data, provides enhanced delimitation of the genomic location of mutations, and greatly reduces hands‐on time while maintaining high accuracy and reproducibility. In this unit, a detailed procedure to simultaneously map and identify EMS mutations in Arabidopsis is described. Curr. Protoc. Mol. Biol. 108:7.18.1‐7.18.16. © 2014 by John Wiley & Sons, Inc.
Protein Synthesis Using a Reconstituted Cell‐Free System
Authors: Tuckey Corinna , Asahara Haruichi , Zhou Ying , Chong Shaorong
Published: October 2014

Most cell‐free protein‐synthesis systems are based on cell extracts, which often contain undesirable activities. Reconstituted systems, by contrast, are composed of a defined number of purified and recombinant components with minimal nuclease and protease activities. This unit describes the use of a particular commercial reconstituted system, PURExpress. This system allows in vitro synthesis of proteins from mRNA and circular and linear DNA templates, as well as co‐translational labeling of proteins. Unique to this system, all recombinant protein components of the system are His‐tagged, allowing purification of the synthesized untagged protein by removing the rest of the system's components. Newly synthesized proteins can often be visible on an SDS‐PAGE gel and directly assayed for their functions without labeling and purification. Certain components of the system, such as ribosomes or release factors, can be omitted for specific applications. Such “delta” versions of the system are well suited for studies of bacterial translation, assays of ribosome function, incorporation of unnatural amino acids, and ribosome display of protein libraries. Curr. Protoc. Mol. Biol. 108:16.31.1‐16.31.22. © 2014 by John Wiley & Sons, Inc.
Genome‐Wide Analysis of Nucleosome Positions, Occupancy, and Accessibility in Yeast: Nucleosome Mapping, High‐Resolution Histone ChIP, and NCAM
Authors: Rodriguez Jairo , McKnight Jeffrey N. , Tsukiyama Toshio
Published: October 2014

Because histones bind DNA very tightly, the location on DNA and the level of occupancy of a given DNA sequence by nucleosomes can profoundly affect accessibility of non‐histone proteins to chromatin, affecting virtually all DNA‐dependent processes, such as transcription, DNA repair, DNA replication and recombination. Therefore, it is often necessary to determine positions and occupancy of nucleosomes to understand how DNA‐dependent processes are regulated. Recent technological advances made such analyses feasible on a genome‐wide scale at high resolution. In addition, we have recently developed a method to measure nuclease accessibility of nucleosomes on a global scale. This unit describes methods to map nucleosome positions, to determine nucleosome density, and to determine nuclease accessibility of nucleosomes using deep sequencing. Curr. Protoc. Mol. Biol. 108:21.28.1‐21.28.16. © 2014 by John Wiley & Sons, Inc.
Confocal Microscopy for High‐Resolution and High‐Content Analysis of the Cell Cycle
Authors: Furia Laura , Pelicci Piergiuseppe , Faretta Mario
Published: October 2014

Optical fluorescence microscopy offers a wide range of technological solutions to address many questions in biomedical research. Spatial resolution has been greatly improved by the use of confocal microscopes, providing a 3‐D analysis of the intracellular space. Automation has contributed to make confocal analysis available for high‐content image cytometry studies. However, the storage, browsing, and analysis of the amount of data generated can challenge the feasibility of such studies. Presented in this chapter is a multistep acquisition and analysis protocol that can bypass such difficulties by an analysis‐driven data collection. Cell‐cycle analysis of low‐resolution data can be employed to select cell populations of interest that can then be imaged at extremely high resolution and subjected to high‐content analysis.Curr. Protoc. Cytom. 70:7.42.1‐7.42.14. © 2014 by John Wiley & Sons, Inc.
Assessing WRF model parameter sensitivity: A case study with 5 day summer precipitation forecasting in the Greater Beijing Area
Authors: Di Zhenhua , Duan Qingyun , Gong Wei , Wang Chen , Gan Yanjun , Quan Jiping , Li Jianduo , Miao Chiyuan , Ye Aizhong , Tong Charles
Published: October 2014

A global sensitivity analysis method was used to identify the parameters of the Weather Research and Forecasting (WRF) model that exert the most influence on precipitation forecasting. Twenty‐three adjustable parameters were selected from seven physical components of the WRF model. The sensitivity was evaluated based on skill scores calculated over nine 5 day precipitation forecasts during the summer seasons from 2008 to 2010 in the Greater Beijing Area in China. We found that eight parameters are more sensitive than others. Storm type seems to have no impact on the list of sensitive parameters but does influence the degree of sensitivity. We also examined the physical interpretation of parameter sensitivity. This analysis is useful for further optimization of the WRF model parameters to improve precipitation forecasting.
Modeling the evolution of climate‐sensitive Arctic subsea permafrost in regions of extensive gas expulsion at the West Yamal shelf
Authors: Portnov Alexey , Mienert Jurgen , Serov Pavel
Published: October 2014

Thawing subsea permafrost controls methane release from the Russian Arctic shelf having a considerable impact on the climate‐sensitive Arctic environment. Expulsions of methane from shallow Russian Arctic shelf areas may continue to rise in response to intense degradation of relict subsea permafrost. Here we show modeling of the permafrost evolution from the Late Pleistocene to present time at the West Yamal shelf. Modeling results suggest a highly dynamic permafrost system that directly responds to even minor variations of lower and upper boundary conditions, e.g., geothermal heat flux from below and/or bottom water temperature changes from above permafrost. Scenarios of permafrost evolution show a potentially nearest landward modern extent of the permafrost at the West Yamal shelf limited by ~17 m isobaths, whereas its farthest seaward extent coincides with ~100 m isobaths. The model also predicts seaward tapering of relict permafrost with a maximal thickness of 275–390 m near the shoreline. Previous field observations detected extensive emissions of free gas into the water column at the transition zone between today's shallow water permafrost (<20 m) and deeper water nonpermafrost areas (>20 m). The model adapts well to corresponding heat flux and ocean temperature data, providing crucial information about the modern permafrost conditions. It shows current locations of upper and lower permafrost boundaries and evidences for possible release of methane from the seabed to the hydrosphere in a warming Arctic.
Alfentanil
Authors: Chen Meixia
Published: October 2014

Alfentanil is a fast‐acting synthetic opioid anesthetic used for minor surgical procedures. Metabolic pathways of alfentanil in vitro in rat and dog hepatocytes, by human liver microsomes, and in vivo in rats, dogs, and humans are shown. The primary metabolic pathways observed were the oxidative N‐dealkylation at the piperidine nitrogen and at the amide nitrogen, oxidative O‐demethylation, aryl hydroxylation, and the formation of glucuronides.
Almotriptan
Authors: Diao Xingxing
Published: October 2014

Almotriptan is a selective serotonin receptor agonist used for the treatment of migraine headache. Its in vitro metabolic pathway in human liver subcellular fractions and in vivo metabolic pathway in rats, dogs, monkeys, and humans are shown. In humans, almotriptan was converted to the carbinolamine metabolite
2
via hydroxylation of the pyrrolidine group. This reaction was mainly catalyzed by CYP3A4 and 2D6. Metabolite
2
was further oxidized by aldehyde dehydrogenase to the open ring γ‐aminobutyric acid derivative
3
. N‐Demethylation at the dimethylamino group to form
4
was carried out by five different CYPs. FMO‐3 mediated N‐oxidation to form metabolite
5
, and MAO‐A catalyzed oxidative deamination to form indole acetic acid
6
and indole ethyl alcohol
7
. Metabolite 6 further formed a glucuronide conjugate.
Asenapine
Authors: Xie Cen
Published: October 2014

Asenapine is an atypical antipsychotic used for the treatment of schizophrenia and acute mania associated with bipolar disorder. The metabolic pathway of asenapine in humans is shown. Asenapine was extensively and rapidly metabolized in humans. The primary metabolic routes were direct glucuronidation at the nitrogen of tetrahydropyrrole ring to form isomeric
N
+
‐glucuronides, hydroxylation and di‐hydroxylation at benzene ring, formylated at the secondary amine, and metabolized to a carbamate glucuronide.
N
‐Formyl‐
N
‐desmethylasenapine was further hydroxylated at both benzene rings to form hydroxyl‐
N
‐formyl‐
N
‐desmethylasenapine. All hydroxylated metabolites underwent further phase II conjugation reactions, including sulfation and glucuronidation, and to a lesser extent, methylation.
N
‐Glucuronides of asenapine were the predominant circulating and urinary components, followed by
N
‐desmethylasenapine‐
N
‐carbamoyl‐glucuronide,
N
‐desmethylasenapine, and asenapine 11‐
O
‐sulfate.
Azelastine
Authors: Xu Lin
Published: October 2014

Azelastine, commonly used as a nasal spray or as eye drops, was mainly metabolized via N‐demethylation by cytochrome P450 enzymes to a pharmacologically active metabolite, desmethylazelastine both in vitro and in vivo metabolism studies.
Benidipine
Authors: Gao Ruina
Published: October 2014

Benidipine is a dihydropyridine calcium channel blocker. It is used as antihypertensive, antianginal, and myocardial protective agents. The in vitro metabolism of benidipine was conducted with pooled human liver microsomes. Primary metabolic pathways included the aromatization of the dihydropyridine ring and N‐dearylation of the benzylpiperidine moiety. CYP3A4 and 3A5 catalyzed the formation of these two metabolites. The in vivo metabolism of [
14
C‐dihydropyridine]‐benidipine was studied in rats, dogs, and humans. In the human metabolism study, seven metabolites were observed, resulting from aromatization, N‐dearylation, and ester hydrolysis. Unchanged drug was not detected in urine and feces.
Bicalutamide
Authors: Xu Lin
Published: October 2014

Bicalutamide was extensively metabolized in humans and animals. Primary metabolic pathways include arylhydroxylation and glucuronidation. Bicalutamide and monohydroxylated metabolite were primarily recovered in feces of all species. Bicalutamide also showed stereospecific metabolism. The pharmacologically active
R
‐enantiomer was mainly hydroxylated to the inactive monohydroxylated metabolite, whereas the inactive
S
‐enantiomer was metabolized primarily by direct glucuronidation.
Boceprevir
Authors: Zhang Zhi‐Yi
Published: October 2014

Boceprevir (brand name: Victrelis), (1
R
,2
S
,5
S
)‐
N
‐((
S
)‐4‐amino‐1‐cyclobutyl‐3,4‐dioxobutan‐2‐yl)‐3‐((
S
)‐2‐(3‐(
tert
‐butyl)ureido)‐3,3‐dimethylbutanoyl)‐6,6‐dimethyl‐3‐azabicyclo[3.1.0] hexane‐2‐carboxamide, is a viral protease inhibitor used to treat chronic hepatitis C. In vitro, the drug undergoes the microsomal oxidation which is mediated by CYP3A4/5 to form a series of diastereomeric cyclobutyl‐hydroxylated metabolites and an amide product, and the cytosolic reduction of the α‐carbonyl group of carboxamide, which is mediated by aldo–keto reductases, AKR1C2, and AKR1C3. In preclinical species, boceprevir exhibited favorable pharmacokinetic properties, for example, appreciated target tissue distribution. In humans, the majority of the drug‐related substances, approximately a half being hydroxylated metabolites, were excreted in feces. The carbonyl‐reduced metabolites, meanwhile, are the major circulating drug‐related compounds. Taking together, the principal clearance of boceprevir in humans is hepatic metabolism, CYP3A4/5‐mediated oxidation, and AKRs‐mediated keto‐reduction. The potential for the metabolism‐associated interactions between boceprevir and other therapeutic agents appears remote.
Brimonidine
Authors: Xu Lin
Published: October 2014

Brimonidine undergoes extensive metabolism. Its primary metabolic pathways are hydroxylation and oxidation. Oxobrimonidine and 2,3‐dioxobrimonidine, catalyzed by aldehyde oxidase, are the major metabolites in humans and animals. Monohydroxylation and subsequent glucuronide conjugation also occur at the bromo‐phenyl group.
Budesonide
Authors: Xu Lin
Published: October 2014

Budesonide showed stereoselective metabolism. Its 22
R
‐epimer was converted to 16α‐hydroxyprednisolone, whereas its 22
S
‐epimer was converted to 6β‐hydroxybudesonide. The formation of both metabolites was catalyzed by the CYP3A subfamily in humans.
Captopril
Authors: Yuan Tao
Published: October 2014

Captopril is an angiotensin‐converting enzyme inhibitor, mainly used for the treatment of various forms of hypertension and congestive heart failure.
S
‐Methylated captopril was the major product detected when captopril was incubated with microsomal fractions from human liver, kidney, and intestinal mucosa specimens. The ethyl ester of the
S
‐methylated captopril was also detected from the in vitro study. A high level of protein binding was observed when [
14
C‐carbonyl]‐captopril was incubated with rat plasma and tissue homogenates, 8–54% were covalently bound to plasma and tissue proteins. After oral administration of [
14
C‐carbonyl]‐captopril in rats, approximately 50% of the administrated radioactivity was recovered in urine and feces, respectively. Bile elimination accounted for <10% of the dose. Unchanged captopril, captopril dimmer, and captopril–cysteine conjugate were detected as major metabolites. The disulfide conjugate with glutathione was detected in lung, liver, and small intestine tissues.
Cibenzoline
Authors: Xie Cen
Published: October 2014

Cibenzoline is a highly active class I antiarrhythmic agent. The in vitro metabolism of cibenzoline was investigated in human and rat hepatic microsomes and with cell‐expressed human cytochrome P450s. Major metabolites were
p
‐hydroxycibenzoline (catalyzed by CYP2D6) and 4,5‐dehydrocibenzoline (catalyzed by CYP3A4). The disposition of cibenzoline following a single oral dose of [
14
C]‐cibenzoline was studied in healthy adult males. After 6 days, 86 and 14% of the dose were excreted in urine and feces, respectively. In urine, the predominant compound was the unchanged cibenzoline. Minor products were
p
‐hydroxycibenzoline and 4,5‐dehydrocibenzoline, in both free and conjugated forms, and
p
‐hydroxybenzophenone.
Ciprofloxacin
Authors: Penner Natasha
Published: October 2014

Major metabolic pathways of ciprofloxacin include dealkylation, oxidation to lactam, N‐sulfation and formylation.
Clobazam
Authors: Zhang Zhi‐Yi
Published: October 2014

Clobazam, 7‐chloro‐1‐methyl‐5‐phenyl‐1,5‐benzodiazepine‐2,4(3
H
)‐dione, is a nonsteroidal γ‐amino butyric acid (GABA)‐A receptor modulator for the treatment of epilepsy and anxiety disorder. In vitro, the major metabolic pathways appear to be CYP3A4‐, CYP2C19‐, and CYP2B6‐mediated N‐demethylation and CYP2C19‐ and CYP2C18‐mediated 4′‐hydroxylation. Two primary pathways in tandem constitute the secondary pathway besides the cytosolic catechol
O
‐methyltransferase (COMT)‐mediated formation of isomeric
O
‐methyl catechols, presumably following the catechol intermediate. The
N
‐desmethyl and 4′‐hydroxyl metabolites were principal in preclinical species, whilst the former being predominant in humans. The linear dose escalation was observed after single dose administrations in the healthy volunteers, the major metabolite
N
‐desmethyl clobazam, under a multiple dosing regimen, reached steady state much slower compared to clobazam, resulting in the eight‐time higher steady‐state concentration than that of clobazam.
Diazepam
Authors: Deng Pan
Published: October 2014

Diazepam is a benzodiazepine class of compound that could bind to the γ‐amino butyric acid receptor. It is widely used as a muscle relaxant, anxiolytic, sedative, and anticonvulsant. Metabolism of diazepam was studied in cultured hepatocytes from rats, dogs, guinea pigs, rabbits, and humans. Significant species differences were observed. The primary metabolic pathway was N‐demethylation to yield nordiazepam, but the level of metabolite accumulation was species dependent. In vitro studies showed that both CYP2C19 and CYP3A4 were major contributors to the N‐demethylation of diazepam in human microsomal fractions, whereas CYP3A4 was mainly responsible for 3‐hydroxylation. [
3
H]‐Diazepam was orally administered to human volunteers. An average of 71 and 10% of the dose were excreted in urine and feces, respectively. The only labeled compounds detected in human blood were intact diazepam and nordiazepam. In human urine, nordiazepam, 3‐hydroxydiazepam, oxazepam, the
N
‐glucuronide of nordiazepam, and glucuronide conjugates of 3‐hydroxydiazepam and oxazepam were detected.
Diazoxide
Authors: Xie Cen
Published: October 2014

Diazoxide is a potassium channel activator used for hypertensive emergencies and also used to decrease hypoglycemia. The in vitro metabolism of [
14
C]‐diazoxide was investigated in dog liver homogenates, S9 fractions, and microsomes. Methyl hydroxylation and further oxidation yielded 3‐hydroxymethyl diazoxide and 3‐carboxy diazoxide. In the in vivo metabolism of [
14
C]‐diazoxide, marked species differences were found. The primary metabolic pathways in humans were oxidation of the 3‐methyl to the hydroxymethyl and the carboxy derivative, and subsequent
O
‐sulfate conjugation of 3‐hydroxymethyl diazoxide.
Doxazosin
Authors: Liu Ke
Published: October 2014

Doxazosin is a selective α‐1‐adrenergic blocker. It is used to treat hypertension. [
14
C‐2‐Quinazoline]‐doxazosin was administered via oral and intravenous dosing to mice, rats, dogs, and humans. In humans, urine and feces accounted for 9 and 63% of the administered radioactivity, respectively. Unmetabolized doxazosin accounted for 5% in feces. The majority of plasma radioactivity was the unchanged drug. Doxazosin was extensively metabolized. Major metabolic pathways were 6′‐ and 7′‐hydroxylations, and 6‐ and 7‐O‐demethylations. The 6‐ and 7‐O‐demethyl metabolites accounted for 16 and 7% of the oral dose and the 6′‐ and 7′‐hydroxy metabolites accounted for 5 and 7% of the dose, respectively. Minor products were 2‐piperazinyl metabolite, resulting from the cleavage of the amide linkage, and the 2‐amino compound, resulting from the opening of piperazine ring.
Eletriptan
Authors: Diao Xingxing
Published: October 2014

Eletriptan is a selective 5‐hydroxytryptamine 1B/1D receptor agonist used for the acute treatment of migraine in adults. The in vitro metabolism was investigated by incubating eletriptan with human hepatic cytochrome P450 enzymes. The formation of
N
‐desmethyl eletriptan was catalyzed primarily by CYP3A4. The in vivo metabolism of eletriptan was studied in rats, dogs, and humans. In all test species, eletriptan underwent similar extensive metabolism. Principal metabolic reactions included N‐demethylation, N‐oxidation, hydroxylation of the pyrrolidine ring, and formation of a tetracyclic quaternary ammonium metabolite.
Eltrombopag
Authors: Xie Cen
Published: October 2014

Eltrombopag is a nonpeptide thrombopoietin receptor agonist used for the treatment of chronic immune thrombocytopenia. The metabolism of eltrombopag was studied in healthy male volunteers after a single oral dose of [
14
C]‐eltrombopag. The drug was absorbed rapidly but eliminated slowly. Unchanged eltrombopag was the predominant circulating component. Primary metabolic reactions included monooxidation at the
p
‐methyl group of the phenylpyrazolemoiety, acyl glucuronidation, cleavage of the hydrazine linkage followed by glutathione conjugation, and further transformation to form the corresponding glutamyl cysteine and cysteine conjugates. The main route of elimination of radioactivity was fecal (59%), in which the major radiocomponent was the unchanged eltrombopag, accounting for approximately 20% of the administered dose.
Eplerenone
Authors: Meng Jian
Published: October 2014

Eplerenone is an aldosterone antagonist used in the treatment of chronic heart failure. The metabolism of [
14
C]‐eplerenone was studied in healthy subjects after an oral administration. Eplerenone accounted for about 69% of the total radioactivity in plasma. Percentages of the administered dose recovered in urine and feces were 67 and 32%, respectively. Primary metabolic reactions included monohydroxylation at 6β‐ and 21‐positions, and dihydroxylations, hydrolysis by opening of the lactone ring, and reduction of the ketone group to 3α‐ and 3β‐hydroxyl groups. Major metabolites excreted were 6β‐OH‐eplerenone (32%), 21‐OH‐eplerenone (8%), and 6β,21‐di‐OH‐eplerenone (21%). Hydrolytic cleavage of the methyl ester linkage was not observed.
Erdosteine
Authors: Li Liang
Published: October 2014

Erdosteine is a mucolytic drug used to treat chronic bronchitis. Human patients each received a daily oral erdosteine dose of 300 mg for 7 days. The metabolic pathway involved the initial ring‐opening reaction to form the pharmacologically active metabolite N‐(2‐carboxymethylthioacetyl) homocysteine, followed by S‐dealkylation and oxidative dealkylation reactions to yield homocysteine.
Estazolam
Authors: Diao Xingxing
Published: October 2014

Estazolam is used as an anticonvulsant, hypnotic, and muscle relaxant for the short‐term treatment of insomnia. The metabolism and excretion of [
14
C]‐estazolam in human were studied after a single dose of 2 mg to healthy male volunteers. Urinary and fecal excretions accounted for 87 and 4% of the administered radioactivity, respectively. Besides the parent drug, two metabolites 4‐hydroxy‐estazolam and 1‐oxo‐estazolam were detected in human plasma. However, the major metabolite in human urine (accounting for 17% of the dose) was unidentified.
Famotidine
Authors: Liu Jia
Published: October 2014

Famotidine is a histamine H
2
‐receptor antagonist and is used to inhibit stomach acid production. The pharmacokinetics and metabolism of famotidine were studied in human male subjects following a single oral administration of radiolabeled famotidine. Plasma radioactivity was attributed mainly as the unchanged famotidine over the first 8 h. An average of 38 and 51% of the administered radioactivity was recovered in urine and feces, respectively. Approximately, 53% of the urinary radioactivity was identified as the unchanged famotidine. The only metabolite identified was the
S
‐oxide.
Granisetron
Authors: Deng Pan
Published: October 2014

Granisetron is a specific serotonin 5‐HT
3
receptor antagonist used to prevent chemotherapy‐induced emesis. The disposition and metabolic fate of [
14
C‐carbonyl]‐granisetron was studied in rats, dogs, and male human volunteers after intravenous and oral administrations. In human subjects, about 60 and 36% of the dosed radioactivity was recovered in urine and feces, respectively, after i.v. and oral dosings. Unchanged granisetron was excreted mainly in urine (5–25% of the dose). The major metabolites was 7‐hydroxy‐granisetron, with lesser quantities of the 6,7‐dihydrodiol and their conjugates.
Hydrocodone (oxycodone)
Authors: Penner Natasha
Published: October 2014

Hydrocodone is mainly metabolized to the O‐ and N‐demethylated products, oxymorphone and noroxycodone, by CYP2D6 and CYP3A4, respectively.
Ethinylestradiol
Authors: Penner Natasha
Published: October 2014

Ethinylestradiol is extensively metabolized in humans, both by oxidation (at 2 and 4 positions) and by conjugation with sulfate and glucuronide. Sulfates are the major circulating metabolites and glucuronides are predominant in urine. The primary oxidative metabolite of ethinylestradiol is 2‐hydroxy ethinylestradiol formed by the CYP3A4.
Indinavir
Authors: Meng Jian
Published: October 2014

Indinavir is an HIV protease inhibitor used in combination with other drugs to treat human immunodeficiency virus infection and acquired immunodeficiency syndrome. The metabolism of [
14
C]‐indinavir was studied in healthy subjects after oral administration of 400 mg. Intact indinavir accounted for about 53% of the total radioactivity in plasma. Circulating metabolites identified were the
N
‐glucuronide conjugate at the pyridine nitrogen, pyridine
N
‐oxidation metabolite,
p
‐hydroxylation metabolite of the benzyl group, 3′‐
trans
‐hydroxylation metabolite of the indane moiety,
N
‐dealkylation metabolite, and two secondary metabolites. The administered radioactivity was excreted 83% in feces, and 19% in urine.
Ixabepilone
Authors: Gao Chunying
Published: October 2014

Ixabepilone is an epothilone B analog. It is used for the treatment of aggressive metabolic or locally advanced breast cancer no longer responding to currently available chemotherapies. After an intravenous administration of 70 mg of [
14
C]‐ixabepilone to eight patients, approximately 25 and 52% of the administered radioactivity were recovered in urine and feces, respectively, over the 168‐h collection period. In human plasma and urine, the unchanged ixabepilone was the predominant radioactive component. Metabolites produced through rearrangement/cyclization, hydration of the epoxide and hydroxylation/oxidation were detected. In human feces, ixabepilone was detected in a small amount of (<2% of the administered dose), and six metabolites were observed.
Laropiprant
Authors: Meng Jian
Published: October 2014

Laropiprant is a selective antagonist of prostaglandin D2 receptor 1. It is mainly used for the treatment of niacin‐induced flushing. Rapid absorption of the administered laropiprant was observed in six healthy male subjects after a single oral dose of [
14
C‐methylsulfonyl]‐laropiprant. The unchanged [
14
C]‐laropiprant represented 30% of the radioactivity in plasma. The acyl glucuronide conjugate of laropiprant was the only other radiochemical component in plasma. The major route of excretion of radioactivity was via feces (68% of the administered dose). Urinary excretion averaged 22% of the administered dose. The acyl glucuronide conjugate was the major excreted metabolite. Minor metabolites included hydroxylation products and their further keto oxidation product, and glucuronide conjugates of them.
Letosteine
Authors: Liu Jia
Published: October 2014

Letosteine is an expectorant. It dissolves bronchial mucus and reduces respiratory inflammation symptoms. The rat metabolism of [
14
C‐carbonyl]‐letosteine and [
35
S‐thiazolidinyl]‐letosteine was conducted after intravenous (i.v.) and oral (per os (p.o.)) administrations. More than 86% of the administered [
14
C]‐radioactivity was recovered in urine within 72 h after i.v. and p.o. dosings. Approximately, 5–7% of the administered [
14
C]‐radioactivity was recovered as
14
CO
2
in the expired air. Only 40–50% of the administered [
35
S]‐radioactivity was recovered after i.v. and p.o. dosings, indicative of the potential of [
35
S]‐radioactivity incorporation to biological tissues. Elimination of the radioactivity via feces was <10%. Primary metabolic reaction included the initial hydrolysis of the ethyl ester to yield the acid metabolite. Further metabolism yielded the diacid metabolite 3‐(carboxymethylthio)propanoic acid and its S‐oxidation metabolites (sulfoxide and sulfone).
Levofloxacin
Authors: Zhou Xin
Published: October 2014

Levofloxacin is an antibacterial drug used to treat community‐acquired pneumonia, acute bacterial sinusitis, urinary tract infections, and acute pyelonephritis. It was metabolized to its acyl glucuronide by human liver microsomes and cDNA‐expressed recombinant human UDP‐glucuronosyltransferase enzymes (predominantly by UGT1A1, 1A3, and 1A9). The metabolic profile of [
14
C]‐levofloxacin in both rhesus monkeys and humans was examined. Three metabolites were detected in urine, feces, and plasma. Major metabolic reactions included glucuronide conjugation of levofloxacin, N‐demethylation, and N‐oxidation.
Lopinavir
Authors: Dai Jing
Published: October 2014

Lopinavir is a protease inhibitor used in the treatment of human immunodeficiency virus (HIV) at a fixed‐dose combination with ritonavir. It is extensively metabolized primarily by CYP3A subfamily of cytochrome P450 enzymes via oxidation at C‐4 and C‐6 positions on the cyclic urea, dimethyl phenoxy moiety and alkyl linkage, yielding multiple epimers. Fecal excretion is the major route of elimination in vivo, mostly as hydroxylated metabolites.
Norfloxacin
Authors: Zhou Xin
Published: October 2014

Norfloxacin is a synthetic chemotherapeutic agent used to treat urinary tract infections. Human metabolite identification was studied using two norfloxacin formulations. Biotransformation reactions included formylation to yield
N
‐formylnorfloxacin, N‐acetylation to yield
N
‐acetylnorfloxacin, N‐dealkylation to form desethylene‐
N
‐acetylnorfloxacin, and cleavage of the piperazine ring to yield mono‐ and di‐
N
‐deethylation metabolites.
Prazosin
Authors: Liu Ke
Published: October 2014

Prazosin is a selective α‐adrenergic blocker used mainly to treat high blood pressure and anxiety. A complex metabolic profile was observed in rat, dog, and human liver microsomes and hepatocytes. Primary metabolic reactions included the cleavage of the
N
‐furanyl methanone linkage, hydroxylation/dehydration of the piperazine ring, opening of the furan ring, O‐demethylation, followed by glucuronide conjugation, and N‐glucuronidation. It was also found that several GSH conjugates resulted from the opening of the furan ring.
Seliciclib
Authors: Diao Xingxing
Published: October 2014

Seliciclib is a potent cyclin‐dependent kinase inhibitor. It is an experimental anticancer drug. Five major metabolites were identified when human liver microsomes were incubated with [
14
C]‐seliciclib. It included two N‐dealkylation metabolites, a carboxylic metabolite, a side‐chain hydroxylation metabolite, and a ring oxidation metabolite. The formation of these metabolites was catalyzed by CYP3A4/3A5 and 2B6.
Tropisetron
Authors: Deng Pan
Published: October 2014

Tropisetron is a specific serotonin receptor antagonist used to prevent chemotherapy‐induced and postoperative nausea and vomiting. Rapid and extensive absorption of the administered radioactive dose of [
14
C‐carbonyl]‐tropisetron in healthy male volunteers after a single oral administration was observed. More than 90% of the drug was metabolized before excretion and about 70% of the dose was recovered in the urine. The primary metabolic reactions of tropisetron included the hydroxylation at positions 5, 6, and 7 of the indole ring. These hydroxylated metabolites were further conjugated with sulfate and glucuronic acid. The N‐oxidation and N‐demethylation products were detected only in trace level. In the plasma, the 5‐OH‐glucuronide was the most abundant metabolite, followed by the 6‐OH metabolite and its sulfate conjugate.
Venlafaxine
Authors: Dai Jing
Published: October 2014

Venlafaxine inhibits serotonin‐norepinephrine reuptake and is used in the treatment of major depressive, anxiety, and panic disorders. O‐ and N‐demethylation are the two metabolic pathways in vitro and are catalyzed by cytochrome P450 CYP2D6 and CYP3A4, respectively. Further sulfation and glucuronidation of these desmethyl metabolites occurs in vivo.
O
‐Desmethyl venlafaxine is an active metabolite that displays comparable pharmacological activity to that of venlafaxine and is susceptible to polymorphic effects of CYP2D6.
Barnidipine
Authors: Gao Ruina
Published: October 2014

Barnidipine is a calcium antagonist used for the treatment of hypertension. After oral administration of 10‐mg barnidipine hydrochloride to healthy male subjects, plasma and urine samples were collected and analyzed. Hydrolysis of the benzylpyrrolidine ester and aromatization of the dihydropyridine ring to pyridine were the major human metabolic reactions. The plasma concentrations of the metabolite formed by hydrolysis of the benzylpyrrolidine ester and the metabolite formed by aromatization of the dihydropyridine ring were equal to or lower than that of barnidipine. Other metabolites were negligible in plasma. The excretion of unchanged barnidipine in urine was <0.1% of the dose, and the metabolite formed by both hydrolysis of the benzylpyrrolidine ester and aromatization of the dihydropyridine ring was the major urinary metabolite, accounting for 19% of the dose. Other metabolic pathways included N‐debenzylation and hydrolysis of the methyl ester.
Calcipotriene
Authors: Xu Lin
Published: October 2014

Calcipotriene, as an anti‐proliferative agent in the treatment of psoriasis, was metabolized extensively via oxidation reaction to 24‐ketone (2) and reductive reaction to its 22,23‐hydrogenated derivative (3). Both reactions were catalyzed by nonspecific enzymes such as 24‐oxidoreductase and 22,23‐reductase. Further oxidation or side‐chain cleavage via vitamin‐D‐related enzymes yield other metabolites.
Ziprasidone
Authors: Xie Cen
Published: October 2014

Ziprasidone is a second‐generation antipsychotic drug used to treat schizophrenia and acute psychotic episodes. A single dose of 20‐mg ziprasidone labeled with
14
C and
3
H was administered to four healthy subjects. It was extensively metabolized (>95% of the administered dose) in humans, with <5% of the dose excreted as unchanged drug. Numerous metabolites were identified in urine and serum: sulfoxide and sulfone metabolites of ziprasidone, N‐dealkylated metabolites of oxindole‐acetic acid and its glucuronide conjugate, benzisothiazole‐3‐yl‐piperazine (BITP), BITP‐sulfoxide, BITP‐sulfone and its lactam,
S
‐methyl‐dihydro‐ziprasidone and its sulfoxide, a C=N bond hydrated product, and a metabolite formed by dearylation of the benzisothiazole moiety.
S
‐Methyl‐dihydro‐ziprasidone was the major circulating and excretory metabolite.
Carfilzomib
Authors: Gao Chunying
Published: October 2014

Carfilzomib is a selective proteasome inhibitor used for the treatment of multiple myeloma and mantle cell lymphoma. The metabolism of carfilzomib was examined in rats after intravenous administration. Metabolites in the plasma, urine, and bile samples were analyzed. Amide hydrolysis and the opening of the epoxide were the major metabolic pathways observed, which generated numerous metabolites. In addition, hydroxylation of the isobutyl group and the dehydrogenation of the morpholine ring were the minor metabolic pathways. Morpholino‐homophenylalanine, morpholino‐homophenylalanine‐leucine, and the diol of carfilzomib were the most abundant metabolites in both plasma and excreta.
Cladribine
Authors: Diao Xingxing
Published: October 2014

Cladribine is a purine analog drug that suppresses the immune system. It is used to treat hairy cell leukemia and multiple sclerosis. The in vivo metabolism of cladribine was studied in 12 male human patients after an intravenous infusion at 22–45 mg per subject. Six metabolites were detected in human urine, including the N‐dealkylation product 2‐chloroadenine, the metabolite by hydroxylation and oxidation at adenosine, the carboxylic acid metabolite by oxidation at deoxyribose and its glucuronide conjugate, and the glucuronide and sulfate conjugates of cladribine.
Digoxin
Authors: Yang Yong
Published: October 2014

Digoxin is an Na
+
/K
+
pump inhibitor clinically used in the treatment of congestive heart failure and certain cardiac arrhythmias. The stepwise deglycosylation cleavage of the ether linkage of the digitoxoses, which forms digoxigenine–bisdigitoxoside, digoxigenin–monodigitoxoside, and 3β‐digoxigenin, was the major metabolic pathway observed in humans. 3β‐Digoxigenin could be converted to 3α‐digoxigenin via 3‐keto‐digoxigenin catalyzed by human liver alcohol dehydrogenase. Glucuronide and sulfate conjugates of 3β‐ and 3α‐digoxigenins were also found in urine. The lactone ring reduction derivative 20
R
‐dihydrodigoxin was found as a major metabolite in patients treated with digoxin.
Diltiazem
Authors: Deng Pan
Published: October 2014

Diltiazem is a nondihydropyridine calcium channel blocker used for the treatment of angina, hypertension, and certain heart‐rhythm disorders. The metabolism of diltiazem in humans was examined following a single oral dose of 90 mg. N‐Demethylation and N‐deacetylation were the primary metabolic reactions. Diltiazem,
N
‐desmethyl diltiazem, desacetyl diltiazem, and
N
‐desmethyl‐desacetyl diltiazem were detected in human plasma.
N
‐Desmethyl diltiazem was the most abundant metabolite in human plasma and urine. The diltiazem
N
‐oxide and
O
‐demethylated desacetyl diltiazem were observed as minor metabolites.
Diphenhydramine
Authors: Liu Jia
Published: October 2014

Diphenhydramine is a first‐generation antihistamine used to treat numerous allergic ailments. The major metabolite of diphenhydramine in human plasma was (diphenyl‐methoxy)acetic acid. Major human urinary metabolites were (diphenylmethoxy)acetic acid and its glycine conjugate. Diphenhydramine, the
N
‐demethylation metabolite, the quaternary ammonium glucuronide of diphenhydramine, the
N
,
N
‐didemethylation metabolite, and diphenhydramine
N
‐oxide were also detected in human urine.