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Electric Literature of 125995-03-1. Let’s face it, organic chemistry can seem difficult to learn. Especially from a beginner’s point of view. Like 125995-03-1, Name is Atorvastatin lactone. In a document type is Article, introducing its new discovery.

Development, validation and application of a novel HPLC-MS/MS method for the quantification of atorvastatin, bisoprolol and clopidogrel in a large cardiovascular patient cohort

Cardiovascular disease is a leading cause of morbidity, mortality, and healthcare expenditure worldwide. Importantly, there is interindividual variation in response to cardiovascular medications, leading to variable efficacy and adverse events. Therefore a rapid, selective, sensitive and reproducible multi-analyte HPLC-MS/MS assay for the quantification in human plasma of atorvastatin, its major metabolites 2-hydroxyatorvastatin, atorvastatin lactone and 2-hydroxyatorvastatin lactone, plus bisoprolol and clopidogrel-carboxylic acid has been developed, fully validated, and applied to a large patient study. Fifty microliter plasma samples were extracted with a simple protein precipitation procedure involving acetonitrile with acetic acid (0.1%, v/v). Chromatographic separation was via a 2.7 mum Halo C18 (50 × 2.1 mm ID, 90 A) column and gradient elution at a flow rate of 500 muL/min consisting of a mobile phase of water (A) and acetonitrile (B), each containing 0.1% formic acid (v/v), over a 6.0 min run time. The six analytes and their corresponding six deuterated internal standards underwent positive ion electrospray ionisation and were detected with multiple reaction monitoring. The developed method was fully validated with acceptable selectivity, carryover, dilution integrity, and within-run and between-run accuracy and precision. Mean extraction recovery for the analytes was 92.7?108.5%, and internal standard-normalised matrix effects had acceptable precision (coefficients of variation 2.2?12.3%). Moreover, all analytes were stable under the tested conditions. Atorvastatin lactone to acid interconversion was assessed and recommendations for its minimisation are made. The validated assay was successfully applied to analyse 1279 samples from 1024 patients recruited to a cardiovascular secondary prevention prospective study.

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Children learn through play, and they learn more than adults might expect. Science experiments are a great way to spark their curiosity, get their minds active, and encourage them to do something that doesn’t involve a screen. 125995-03-1, C33H33FN2O4. A document type is Article, introducing its new discovery., Safety of Atorvastatin lactone

Statin Lactonization by Uridine 5?-Diphospho-glucuronosyltransferases (UGTs)

Statins are cholesterol-lowering drugs that have proven to be effective in lowering the risk of major cardiovascular events. Although well tolerated, statin-induced myopathies are the most common side effects. Compared to their pharmacologically active acid form, statin lactones are more potent inducers of toxicity. They can be formed by glucuronidation mediated by uridine 5?-diphospho-glucuronosyltransferases (UGTs), but a systematic characterization of subtype specificity and kinetics of lactonization is lacking. Here, we demonstrate for six clinically relevant statins that only UGT1A1, 1A3, and 2B7 contribute significantly to their lactonization. UGT1A3 appeared to have the highest lactonization capacity with marked differences in statin conversion rates: pitavastatin atorvastatin > cerivastatin > lovastatin > rosuvastatin (simvastatin not converted). Using in silico modeling we could identify a probable statin interaction region in the UGT binding pocket. Polymorphisms in these regions of UGT1A1, 1A3, and 2B7 may be a contributing factor in statin-induced myopathies, which could be used in personalization of statin therapy with improved safety.

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A catalyst don’t appear in the overall stoichiometry of the reaction it catalyzes, but it must appear in at least one of the elementary reactions in the mechanism for the catalyzed reaction. 125995-03-1, Name is Atorvastatin lactone, molecular formula is C33H33FN2O4. In a Article£¬once mentioned of 125995-03-1, COA of Formula: C33H33FN2O4

Enniatins (ENNs) are fungal secondary metabolites that frequently occur in grain in temperate climates. Their toxic potency is connected to their ionophoric character and lipophilicity. The biotransformation of ENNs predominantly takes place via cytochrome P450 3A (CYP 3A)-dependent oxidation reactions. Possible interaction with ENNs is relevant since CYP3A4 is the main metabolic enzyme for numerous drugs and contaminants. In the present study, we have determined the kinetic characteristics and inhibitory potential of ENNB1 in human liver microsomes (HLM) and CYP3A4-containing nanodiscs (ND). We showed in both in vitro systems that ENNB1 is mainly metabolised by CYP3A4, producing at least eleven metabolites. Moreover, ENNB1 significantly decreased the hydroxylation rates of the typical CYP3A4-substrate midazolam (MDZ). Deoxynivalenol (DON), which is the most prevalent mycotoxin in grain and usually co-occurrs with the ENNs, was not metabolised by CYP3A4 or binding to its active site. Nevertheless, DON affected the efficiency of this biotransformation pathway both in HLM and ND. The metabolite formation rates of ENNB1 and the frequently used drugs progesterone (PGS) and atorvastatin (ARVS) lactone were noticeably reduced, which indicated a certain affinity of DON to the enzyme with subsequent conformational changes. Our results emphasise the importance of drug?drug interaction studies, also with regard to natural toxins.

Balanced chemical reaction does not necessarily reveal either the individual elementary reactions by which a reaction occurs or its rate law.COA of Formula: C33H33FN2O4. In my other articles, you can also check out more blogs about 125995-03-1

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Synthetic Route of 125995-03-1, Catalysts are substances that increase the reaction rate of a chemical reaction without being consumed in the process. 125995-03-1, Name is Atorvastatin lactone, molecular formula is C33H33FN2O4. In a Article£¬once mentioned of 125995-03-1

Atorvastatin belongs to the group of lipid-lowering drugs known as statins. They significantly reduce the levels of total cholesterol, low-density cholesterol and plasma triglycerides therefore they are widely used in the treatment of hypercholesterolemia. Recently developed methods for the determination of atorvastatin and its metabolites in plasma used SPE (solid phase extraction) or LLE (liquid-liquid extraction) as the sample preparation step. However, both procedures are quite time-consuming and need relatively high volume of solvent/sample, which is impractical for the routine analyses of many biological samples.The aim of this work was to develop and validate more suitable sample preparation method for the determination of atorvastatin and its metabolites in biological samples using MEPS (microextraction by packed sorbent). The optimal conditions of MEPS extraction were using C8 sorbent and only 50mul of the sample. The analytes were eluted by 100mul of the mixture of acetonitrile:0.1M ammonium acetate pH 4.5 (95:5, v:v). The analytical method was validated and demonstrated good linearity (r2>0.9990), recovery (89-115%) and intra-day precision (RSD<10%). Total time of the sample preparation was three times shorter (7min) compared to SPE. The volume of sample was twenty times lower and the volume of solvents about ten times lower compared to SPE. Combination of fast MEPS method together with quick UHPLC-MS/MS was used for the determination of atorvastatin and its two metabolites in serum obtained from patients with familiar hypercholesterolemia. The proportionality constant is the rate constant for the particular unimolecular reaction. the reaction rate is directly proportional to the concentration of the reactant. I hope my blog about 125995-03-1 is helpful to your research., Synthetic Route of 125995-03-1

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Tetrahydropyran – Wikipedia,
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Electric Literature of 125995-03-1, Catalysts are substances that increase the reaction rate of a chemical reaction without being consumed in the process. 125995-03-1, Name is Atorvastatin lactone, molecular formula is C33H33FN2O4. In a Article£¬once mentioned of 125995-03-1

The drug?drug interaction profile of atorvastatin confirms that disposition is determined by cytochrome P450 (CYP) 3A4 and organic anion transporting polypeptides (OATPs). Drugs that affect gastric emptying, including dulaglutide, also affect atorvastatin pharmacokinetics (PK). Atorvastatin is a carboxylic acid that exists in equilibrium with a lactone form in vivo. The purpose of this work was to assess gastric acid?mediated lactone equilibration of atorvastatin and incorporate this into a physiologically-based PK (PBPK) model to describe atorvastatin acid, lactone, and their major metabolites. In vitro acid-to-lactone conversion was assessed in simulated gastric fluid and included in the model. The PBPK model was verified with in vivo data including CYP3A4 and OATP inhibition studies. Altering the gastric acid?lactone equilibrium reproduced the change in atorvastatin PK observed with dulaglutide. The model emphasizes the need to include gastric acid?lactone conversion and all major atorvastatin-related species for the prediction of atorvastatin PK.

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Tetrahydropyran – Wikipedia,
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In an article, published in an article, once mentioned the application of 125995-03-1, Name is Atorvastatin lactone,molecular formula is C33H33FN2O4, is a conventional compound. this article was the specific content is as follows.name: Atorvastatin lactone

A series of trans-tetrahydro-4-hydroxy-6-<2-(2-(2,3,4,5-substituted-1H-pyrrol-1-yl)ethyl>-2H-pyran-2 ones and their dihydroxy acids were prepared and tested for their ability to inhibit the enzyme HMG-CoA reductase in vitro.Inhibitory potency was found to increase subtantially when substituents were introduced into positions three and four of the pyrrole ring.A systematic exploration of structure-activity relationships at these two positions led to the identification of a compound ((+)-33, (+)-(4R)-trans-2-(4-fluorophenyl)-5-(1-methylethyl)-N,3-diphenyl-1-<(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl> -1H-pyrrole-4-carboxamide) with five times the inhibitory potency of the fungal metabolite compactin.

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Related Products of 125995-03-1, Children learn through play, and they learn more than adults might expect. Science experiments are a great way to spark their curiosity, get their minds active, and encourage them to do something that doesn’t involve a screen. 125995-03-1, C33H33FN2O4. A document type is Article, introducing its new discovery.

Statins are lipid-lowering drugs used widely to prevent and treat cardiovascular and coronary heart diseases. These drugs are among the most commonly prescribed medicines intended for long-term use. In general, statins are well tolerated. However, muscular adverse effects appear to be the most common obstacle that limits their use, resulting in poor patient compliance or even drug discontinuation. In addition, rare but potentially fatal cases of rhabdomyolysis have been reported with the use of these drugs, especially in the presence of certain risk factors. Previous reports have investigated statin-induced myotoxicity in vivo and in vitro using a number of cell lines, muscle tissues, and laboratory animals, in addition to randomized clinical trials, observational studies, and case reports. None of them have compared directly results from laboratory investigations with clinical observations of statin-related muscular adverse effects. To the best of our knowledge this is the first review article that combines laboratory investigation with clinical aspects of statin-induced myotoxicity. By reviewing published literature of in vivo, in vitro, and clinically relevant studies of statin myotoxicity, we aim to translate this important drug-related problem to establish a clear picture of proposed mechanisms that explain the risk factors and describe the diagnostic approaches currently used for evaluating the degree of muscle damage induced by these agents. This review provides baseline novel translational insight that can be used to enhance the safety profile, to minimize the chance of progression of these adverse effects to more severe and potentially fatal rhabdomyolysis, and to improve the overall patient compliance and adherence to long-term statin therapy.

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The reaction rate of a catalyzed reaction is faster than the reaction rate of the uncatalyzed reaction at the same temperature.125995-03-1, Name is Atorvastatin lactone, molecular formula is C33H33FN2O4. In a Article£¬once mentioned of 125995-03-1, Safety of Atorvastatin lactone

Cytochrome P450 (CYP450) enzymes belong to a superfamily of heme-containing proteins that are involved in the metabolism of structurally diverse endogenous and exogenous compounds. Various proof-of-concept studies indicate that metabolic stability and intrinsic clearance of CYP450 substrates are linked with the respective lipophilicity (loga??P or loga??D). This necessitates the normalization of lipophilicity (loga??P or loga??D) of a given CYP450 substrate with respect to its metabolic stability (LipMetE) and intrinsic clearance (log10CLint,u). Therefore, in this article, the LipMetE values of already known substrates of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, including some marketed drugs, have been calculated to elucidate the relationship between lipophilicity (loga??D7.4) and in vitro clearance. Moreover, various drug efficiency metrics including lipophilic efficiency (LipE) and ligand efficiency (LE) have been evaluated, and the thresholds of these parameters have been defined for the CYP450 substrates exhibiting normalized LipMetE. Our results indicate that for a given range of LipMetE, greater the loga??D value of the substrate the more avidly it binds to a given CYP450 enzyme and shows more intrinsic clearance (log10CLint,u). Overall, the majority of the model substrates of CYP450 isoforms and already marketed drugs in our datasets exhibit loga??D7.4 values of a?2.5 with LipMetE values in the range of 0-2.5 and LipE values of ?3. Overall, consideration of these parameters in ADME profiling could aid in reducing the drug failure rate in the later stages of clinical investigations.

The reactant in an enzyme-catalyzed reaction is called a substrate. Enzyme inhibitors cause a decrease in the reaction rate of an enzyme-catalyzed reaction.I hope my blog about 125995-03-1 is helpful to your research., Safety of Atorvastatin lactone

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Tetrahydropyran – Wikipedia,
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Children learn through play, and they learn more than adults might expect. Science experiments are a great way to spark their curiosity, get their minds active, and encourage them to do something that doesn¡¯t involve a screen. 125995-03-1, C33H33FN2O4. A document type is Article, introducing its new discovery., Recommanded Product: 125995-03-1

A concise and convergent synthesis of the atorvastatin, the best-selling cardiovascular drug of all time, is presented. Our approach is based on an Ugi reaction, which shortens the current synthetic route and is advantageous over the published syntheses.

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In an article, published in an article, once mentioned the application of 125995-03-1, Name is Atorvastatin lactone,molecular formula is C33H33FN2O4, is a conventional compound. this article was the specific content is as follows.Product Details of 125995-03-1

Gemfibrozil coadministration generally results in plasma statin area under the curve (AUC) increases, ranging from moderate (2-to 3-fold) with simvastatin, lovastatin, and pravastatin to most significant with cerivastatin (5.6-fold). Inhibition of statin glucuronidation has been postulated as a potential mechanism of interaction (Drug Metab Dispos 30:1280-1287, 2002). This study was conducted to determine the in vitro inhibitory potential of fibrates toward atorvastatin glucuronidation. [3H]Atorvastatin, atorvastatin, and atorvastatin lactone were incubated with human liver microsomes or human recombinant UDP-glucuronosyltransferases (UGTs) and characterized using liquid chromatography (LC)/tandem mass spectrometry and LC/UV/beta-radioactivity monitor/mass spectrometry. [3H]Atorvastatin yields a minor ether glucuronide (G1) and a major acyl glucuronide (G2) with subsequent pH-dependent lactonization of G2 to yield atorvastatin lactone. Atorvastatin lactonization best fit substrate inhibition kinetics (Km = 12 muM, V max = 74 pmol/min/mg, Ki = 75 muM). Atorvastatin lactone yields a single ether glucuronide (G3). G3 formation best fit Michaelis-Menten kinetics (Km = 2.6 muM, Vmax = 10.6 pmol/min/mg). Six UGT enzymes contribute to atorvastatin glucuronidation with G2 and G3 formation catalyzed by UGTs 1A1, 1A3, 1A4, 1A8, and 2B7, whereas G1 formation was catalyzed by UGTs 1A3, 1A4, and 1A9. Gemfibrozil, fenofibrate, and fenofibric acid inhibited atorvastatin lactonization with IC50 values of 346, 320, and 291 muM, respectively. Based on unbound fibrate concentrations at the inlet to the liver, these data predict a small increase in atorvastatin AUC (?1.2-fold) after gemfibrozil coadministration and no interaction with fenofibrate. This result is consistent with recent clinical reports indicating minimal atorvastatin AUC increases (?1.2- to 1.4-fold) with gemfibrozil. Copyright

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