| Size | Price | Stock | Qty |
|---|---|---|---|
| 1g |
|
||
| 2g |
|
||
| 5g |
|
||
| 10g |
|
||
| 25g |
|
||
| Other Sizes |
|
Atorvastatin calcium trihydrate (CI-981) is a potent and selective inhibitor of HMG-CoA reductase primarily used as a cholesterol-lowering medication that blocks the production of cholesterol. Atorvastatin is used primarily for lowering blood cholesterol and for prevention of events associated with cardiovascular disease. As with all statins, atorvastatin works by inhibiting HMG-CoA reductase, an enzyme found in liver tissue that plays a key role in production of cholesterol in the body.
| Targets |
HMG-CoA reductase; HMG-CoA/3-hydroxy-3-methylglutaryl coenzyme A
|
|---|---|
| ln Vitro |
By downregulating the expression of GRP78, caspase-12, and CHOP in cardiomyocytes during myocardial infarction, atorvastatin treatment lowers cardiomyocyte apoptosis. Additionally, it stimulates the endoplasmic reticulum (ER) in response to heart failure and angiotensin II (Ang II) stimulation. ) tension[4].
|
| ln Vivo |
Treatment with atorvastatin (20–30 mg/kg; oral gavage; once daily; for 28 days; ApoE−/− mice) markedly decreased the amount of apoptotic cells, endoplasmic reticulum (ER) stress signaling proteins, and Caspase12 and Caspase12 activation. Bax in ApoE-/- mice triggered by Ang II. Following atorvastatin treatment, pro-inflammatory cytokines such IL-6, IL-8, and IL-1β were markedly suppressed [5].
The effects of orally administered atorvastatin on inflammatory mechanical hypernociception in mouse paws were evaluated with an electronic pressure-meter. Cytokines and PGE(2) were measured by ELISA and RIA. Key results: Treatment with atorvastatin for 3 days dose-dependently reduced hypernociception induced by lipopolysaccharide (LPS) or that following antigen challenge in sensitized animals. Atorvastatin pre-treatment reduced hypernociception induced by bradykinin and cytokines (TNF-alpha, IL-1beta and KC), and the release of IL-1beta and PGE(2) in paw skin, induced by lipopolysaccharide. The antinociceptive effect of atorvastatin on LPS-induced hypernociception was prevented by mevalonate co-treatment without affecting serum cholesterol levels. Hypernociception induced by PGE(2) was inhibited by atorvastatin, suggesting intracellular antinociceptive mechanisms for atorvastatin. The antinociceptive effect of atorvastatin upon LPS- or PGE(2)-induced hypernociception was prevented by non-selective inhibitors of nitric oxide synthase (NOS) but not by selective inhibition of inducible NOS or in mice lacking this enzyme.[1] |
| Cell Assay |
Cell proliferation assays were performed essentially as described previously. Briefly, SV-SMC from 5 different patients were seeded into 24-well cell culture plates at a density of 1 × 104 cells per well in full growth medium. Cells were incubated overnight and then quiesced in serum free medium for 3 days before transfer to full growth medium (10% FCS) containing 5 different statins at a range of concentrations. All statins were tested on cells from each individual patient. Medium and drugs were replaced after 2 days, and viable cell numbers were determined in triplicate wells after 4 days using Trypan Blue and a hemocytometer. The increase in cell number was calculated by subtracting the starting cell number (day 0) from the final cell number (day 4). Data were then normalized to control values (no statin) to correct for differences in proliferation rates between cells from different patients [2].
|
| Animal Protocol |
Effect of atorvastatin on hypernociception induced by LPS or antigen challenge [1]
To investigate the effect of atorvastatin on lipopolysaccharide (LPS)-induced inflammatory hypernociception, mice were pretreated orally with either atorvastatin, at doses of 1, 3, 10, 30 and 90 mg kg−1 or vehicle (PBS) once a day for 3 consecutive days. At 2 h after the last dose of atorvastatin, mice received an i.pl. injection of LPS (100 ng paw−1) or saline (vehicle for LPS). The animals were also treated with atorvastatin (30 mg kg−1) for 1 or 2 days before LPS challenge. The hypernociceptive responses were assessed 0.5, 1, 3, 5, 7 and 24 h after LPS or saline i.pl. injections. In addition, we investigated the effect of atorvastatin on the immune inflammatory hypernociception in mice sensitized to mBSA and challenged with antigen. The animals were pretreated orally with atorvastatin (30 mg kg−1) or PBS once a day for 3 consecutive days. At 2 h after the last dose of atorvastatin, mice received an i.pl. injection of mBSA (90 μg paw−1) or saline. In the control group, mBSA was injected into the paws of the false immunized mice (see above). Mice were fasted for 8 h receiving atorvastatin or PBS. The hypernociceptive responses were assessed 1, 3 and 5 h after challenge with antigen.
|
| ADME/Pharmacokinetics |
Atorvastatin presents a dose-dependent and non-linear pharmacokinetic profile. It is very rapidly absorbed after oral administration. After the administration of a dose of 40 mg, its peak plasma concentration of 28 ng/ml is reached 1-2 hours after initial administration with an AUC of about 200 ng∙h/ml. Atorvastatin undergoes extensive first-pass metabolism in the wall of the gut and the liver, resulting in an absolute oral bioavailability of 14%. Plasma atorvastatin concentrations are lower (approximately 30% for Cmax and AUC) following evening drug administration compared with morning. However, LDL-C reduction is the same regardless of the time of day of drug administration. Administration of atorvastatin with food results in prolonged Tmax and a reduction in Cmax and AUC. Breast Cancer Resistance Protein (BCRP) is a membrane-bound protein that plays an important role in the absorption of atorvastatin. Evidence from pharmacogenetic studies of c.421C>A single nucleotide polymorphisms (SNPs) in the gene for BCRP has demonstrated that individuals with the 421AA genotype have reduced functional activity and 1.72-fold higher AUC for atorvastatin compared to study individuals with the control 421CC genotype. This has important implications for the variation in response to the drug in terms of efficacy and toxicity, particularly as the BCRP c.421C>A polymorphism occurs more frequently in Asian populations than in Caucasians. Other statin drugs impacted by this polymorphism include [fluvastatin], [simvastatin], and [rosuvastatin]. Genetic differences in the OATP1B1 (organic-anion-transporting polypeptide 1B1) hepatic transporter encoded by the SCLCO1B1 gene (Solute Carrier Organic Anion Transporter family member 1B1) have been shown to impact atorvastatin pharmacokinetics. Evidence from pharmacogenetic studies of the c.521T>C single nucleotide polymorphism (SNP) in the gene encoding OATP1B1 (SLCO1B1) demonstrated that atorvastatin AUC was increased 2.45-fold for individuals homozygous for 521CC compared to homozygous 521TT individuals. Other statin drugs impacted by this polymorphism include [simvastatin], [pitavastatin], [rosuvastatin], and [pravastatin].
Route of Elimination Atorvastatin and its metabolites are mainly eliminated in the bile without enterohepatic recirculation. The renal elimination of atorvastatin is very minimal and represents less than 1% of the eliminated dose. Volume of Distribution The reported volume of distribution of atorvastatin is of 380 L. Clearance The registered total plasma clearance of atorvastatin is of 625 ml/min. /MILK/ In a separate experiment, a single dose of 10 mg/kg atorvastatin administered to female Wistar rats on gestation day 19 or lactation day 13 provided evidence of placental transfer and excretion into the milk. PMID:9520344 Lipitor and its metabolites are eliminated primarily in bile following hepatic and/or extra-hepatic metabolism; however, the drug does not appear to undergo enterohepatic recirculation. ... Less than 2% of a dose of Lipitor is recovered in urine following oral administration. /MILK/ It is not known whether atorvastatin is excreted in human milk, but a small amount of another drug in this class does pass into breast milk. Nursing rat pups had plasma and liver drug levels of 50% and 40%, respectively, of that in their mother's milk. Mean volume of distribution of Lipitor is approximately 381 liters. Lipitor is >/= 98% bound to plasma proteins. A blood/plasma ratio of approximately 0.25 indicates poor drug penetration into red blood cells. For more Absorption, Distribution and Excretion (Complete) data for ATORVASTATIN (8 total), please visit the HSDB record page. View More
Metabolism / Metabolites
Biological Half-Life The half-life of atorvastatin is 14 hours while the half-life of its metabolites can reach up to 30 hours. /MILK/ ...After administration to lactating rats, radioactivity in milk reached the maximum of 17.1 ng eq./mL at 6.0 hr and thereafter declined with a half-life of 7.8 hr. Nemoto H et al; Yakuri To Chiryo 26 (7): 79-96 (1998) Mean plasma elimination half-life of Lipitor in humans is approximately 14 hours, but the half-life of inhibitory activity for HMG-CoA reductase is 20 to 30 hours due to the contribution of active metabolites. |
| Toxicity/Toxicokinetics |
Toxicity Summary
IDENTIFICATION AND USE: Atorvastatin is anticholesteremic agent and hydroxymethylglutaryl-CoA reductase inhibitor. HUMAN EXPOSURE AND TOXICITY: Cases of fatal and nonfatal hepatic failure have been reported rarely in patients receiving statins, including atorvastatin. Rhabdomyolysis with acute renal failure secondary to myoglobinuria also has been reported rarely in patients receiving statins, including atorvastatin. Lipid lowering drugs offer no benefit during pregnancy because cholesterol and cholesterol derivatives are needed for normal fetal development. Atherosclerosis is a chronic process, and discontinuation of lipid-lowering drugs during pregnancy should have little impact on long-term outcomes of primary hypercholesterolemia therapy. The occurrence of neuropsychiatric reactions is associated with statin treatment. They include behavioral alterations; cognitive and memory impairments; sleep disturbance; and sexual dysfunction. ANIMAL STUDIES: In a 2-year carcinogenicity study in rats at dose levels of 10, 30, and 100 mg/kg/day, 2 rare tumors were found in muscle in high-dose females: in one, there was a rhabdomyosarcoma, and in another, there was a fibrosarcoma. Atorvastatin caused no adverse effects on semen parameters, or reproductive organ histopathology in dogs given doses of 10, 40, or 120 mg/kg for two years. Male rats given 100 mg/kg/day for 11 weeks prior to mating had decreased sperm motility, spermatid head concentration, and increased abnormal sperm. Studies in rats performed at doses up to 175 mg/kg produced no changes in fertility. There was aplasia and aspermia in the epididymis of 2 of 10 rats treated with 100 mg/kg/day of atorvastatin for 3 months; testis weights were significantly lower at 30 and 100 mg/kg and epididymal weight was lower at 100 mg/kg. In a study in rats given 20, 100, or 225 mg/kg/day, from gestation day 7 through to lactation day 21 (weaning), there was decreased pup survival at birth, neonate, weaning, and maturity in pups of mothers dosed with 225 mg/kg/day. Body weight was decreased on days 4 and 21 in pups of mothers dosed at 100 mg/kg/day; pup body weight was decreased at birth and at days 4, 21, and 91 at 225 mg/kg/day. Pup development was delayed. In vitro, atorvastatin was not mutagenic or clastogenic in the following tests with and without metabolic activation: the Ames test with Salmonella typhimurium and Escherichia coli, the HGPRT forward mutation assay in Chinese hamster lung cells, and the chromosomal aberration assay in Chinese hamster lung cells. Atorvastatin was negative in the in vivo mouse micronucleus test. Atorvastatin selectively and competitively inhibits the hepatic enzyme HMG-CoA reductase. As HMG-CoA reductase is responsible for converting HMG-CoA to mevalonate in the cholesterol biosynthesis pathway, this results in a subsequent decrease in hepatic cholesterol levels. Decreased hepatic cholesterol levels stimulates upregulation of hepatic LDL-C receptors which increases hepatic uptake of LDL-C and reduces serum LDL-C concentrations. Hepatotoxicity Atorvastatin therapy is associated with mild, asymptomatic and usually transient serum aminotransferase elevations in 1% to 3% of patients but levels above 3 times ULN in less than 1%. In summary analyses of large scale studies with prospective monitoring, ALT elevations above 3 times the upper limit of normal (ULN) occurred in 0.7% of atorvastatin treated versus 0.3% of placebo recipients. These elevations were more common with higher doses of atorvastatin, being 2.3% with 80 mg daily. Most elevations were self-limited and did not require dose modification. Atorvastatin is also associated with frank, clinically apparent hepatic injury but this is rare, occurring in ~1:3000 to 1:5000 treated patients. The clinical presentation of atorvastatin hepatotoxicity varies greatly from simple cholestatic hepatitis, to mixed forms, to frankly hepatocellular injury. The latency to onset of injury is also highly variable ranging from 1 month to several years. However, most cases arise within 6 months of starting atorvastatin or several months after a dose escalation. The most common presentation is a cholestatic hepatitis that tends to be mild to moderate in severity and self-limiting in course (Cases 1 and 2). Atorvastatin hepatotoxicity can also present with a distinctly hepatocellular pattern of injury with marked elevations in serum aminotransferase levels and minimal or no increase in alkaline phosphatase. Rash, fever and eosinophilia are uncommon, but at least one-third of hepatocellular cases have features of autoimmunity, marked by high immunoglobulin levels, ANA positivity and liver biopsy findings of autoimmune hepatitis (Cases 3 and 4). These autoimmune cases usually resolve once atorvastatin is stopped, although they may require corticosteroid therapy for resolution. Strikingly, however, some cases of apparent autoimmune hepatitis caused by atorvastatin do not resolve with stopping the medication but are self-sustained and require long term immunosuppressive therapy. It is unclear whether these cases of persistent autoimmune hepatitis caused by the statin therapy or are triggered by statin in a susceptible host. Another possibility is that the association is coincidental and represents a de novo onset of autoimmune hepatitis in someone who happens to be taking a statin. Likelihood score: A (well known cause of clinically apparent liver injury). View More
Effects During Pregnancy and Lactation
Protein Binding Atorvastatin is highly bound to plasma proteins and over 98% of the administered dose is found in a bound form. |
| References |
[1]. Santodomingo-Garzón T, et al. Atorvastatin inhibits inflammatory hypernociception. Br J Pharmacol. 2006 Sep;149(1):14-22.
[2]. Turner NA, et al. Comparison of the efficacies of five different statins on inhibition of human saphenous vein smooth muscle cell proliferation and invasion. J Cardiovasc Pharmacol. 2007 Oct;50(4):458-61. [3]. Nawrocki, J.W., et al., Reduction of LDL cholesterol by 25% to 60% in patients with primary hypercholesterolemia by atorvastatin, a new HMG-CoA reductase inhibitor. Arterioscler Thromb Vasc Biol, 1995. 15(5): p. 678-82. [4]. Song XJ, et al. Atorvastatin inhibits myocardial cell apoptosis in a rat model with post-myocardial infarction heart failure by downregulating ER stress response. Int J Med Sci. 2011;8(7):564-72. [5]. Li Y, et al. Inhibition of endoplasmic reticulum stress signaling pathway: A new mechanism of statins to suppress the development of abdominal aortic aneurysm. PLoS One. 2017 Apr 3;12(4):e0174821. [6]. Ming-Bai Hu, et al. Atorvastatin induces autophagy in MDA-MB-231 breast cancer cells. Ultrastruct Pathol. Sep-Oct 2018;42(5):409-415. [7]. In Vitro Screening for β-Hydroxy-β-methylglutaryl-CoA Reductase Inhibitory and Antioxidant Activity of Sequentially Extracted Fractions of Ficus palmata Forsk. Biomed Res Int. 2014; 2014: 762620. |
| Additional Infomation |
Atorvastatin calcium trihydrate is a hydrate that is the trihydrate form of atorvastatin calcium. It has a role as an environmental contaminant and a xenobiotic. It is a hydrate and a statin (synthetic). It contains an atorvastatin calcium.
Atorvastatin Calcium is the calcium salt of atorvastatin, a synthetic lipid-lowering agent. Atorvastatin competitively inhibits hepatic hydroxymethyl-glutaryl coenzyme A (HMG-CoA) reductase, the enzyme which catalyzes the conversion of HMG-CoA to mevalonate, a key step in cholesterol synthesis. This agent increases the number of LDL receptors on hepatic cell surfaces, enhancing the uptake and catabolism of LDL and reducing LDL production and the number of LDL particles, and lowers plasma cholesterol and lipoprotein levels. Like other statins, atorvastatin may also display direct antineoplastic activity, possibly by inhibiting farnesylation and geranylgeranylation of proteins such as small GTP-binding proteins, which may result in the arrest of cells in the G1 phase of the cell cycle. This agent may also sensitize tumor cells to cyctostatic drugs, possibly through the mTOR-dependent inhibition of Akt phosphorylation. A pyrrole and heptanoic acid derivative, HYDROXYMETHYLGLUTARYL-COA REDUCTASE INHIBITOR (statin), and ANTICHOLESTEREMIC AGENT that is used to reduce serum levels of LDL-CHOLESTEROL; APOLIPOPROTEIN B; and TRIGLYCERIDES. It is used to increase serum levels of HDL-CHOLESTEROL in the treatment of HYPERLIPIDEMIAS, and for the prevention of CARDIOVASCULAR DISEASES in patients with multiple risk factors. See also: Atorvastatin (has active moiety); Atorvastatin calcium trihydrate; ezetimibe (component of). Drug Indication Pure hypercholesterolaemia (heterozygous, homozygous, or otherwise primary hypercholesterolaemia), combined (mixed) hyperlipidaemia; prevention of cardiovascular events |
| Molecular Formula |
C66H74CAF2N4O13
|
|---|---|
| Molecular Weight |
1209.3876
|
| Exact Mass |
1208.484
|
| Elemental Analysis |
C, 65.55; H, 6.17; Ca, 3.31; F, 3.14; N, 4.63; O, 17.20
|
| CAS # |
344423-98-9
|
| Related CAS # |
134523-03-8 (calcium);344423-98-9 (calcium trihydrate);134523-00-5 (free acid);134523-01-6 (sodium); 874114-41-7 (magnesium);
|
| PubChem CID |
656846
|
| Appearance |
Typically exists as White to off-white solid at room temperature
|
| LogP |
9.91
|
| Hydrogen Bond Donor Count |
9
|
| Hydrogen Bond Acceptor Count |
15
|
| Rotatable Bond Count |
22
|
| Heavy Atom Count |
86
|
| Complexity |
817
|
| Defined Atom Stereocenter Count |
4
|
| SMILES |
[Ca+2].FC1C([H])=C([H])C(=C([H])C=1[H])C1=C(C2C([H])=C([H])C([H])=C([H])C=2[H])C(C(N([H])C2C([H])=C([H])C([H])=C([H])C=2[H])=O)=C(C([H])(C([H])([H])[H])C([H])([H])[H])N1C([H])([H])C([H])([H])[C@]([H])(C([H])([H])[C@]([H])(C([H])([H])C(=O)[O-])O[H])O[H].FC1C([H])=C([H])C(=C([H])C=1[H])C1=C(C2C([H])=C([H])C([H])=C([H])C=2[H])C(C(N([H])C2C([H])=C([H])C([H])=C([H])C=2[H])=O)=C(C([H])(C([H])([H])[H])C([H])([H])[H])N1C([H])([H])C([H])([H])[C@]([H])(C([H])([H])[C@]([H])(C([H])([H])C(=O)[O-])O[H])O[H].O([H])[H].O([H])[H].O([H])[H]
|
| InChi Key |
SHZPNDRIDUBNMH-NIJVSVLQSA-L
|
| InChi Code |
InChI=1S/2C33H35FN2O5.Ca.3H2O/c2*1-21(2)31-30(33(41)35-25-11-7-4-8-12-25)29(22-9-5-3-6-10-22)32(23-13-15-24(34)16-14-23)36(31)18-17-26(37)19-27(38)20-28(39)40/h2*3-16,21,26-27,37-38H,17-20H2,1-2H3,(H,35,41)(H,39,40)3*1H2/q+2/p-2/t2*26-,27-/m11..../s1
|
| Chemical Name |
calcium
(3R,5R)-7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoate
trihydrate
|
| Synonyms |
liptonorm; CI-981; CI 981; CI981; Atorvastatin; atorvastatin calcium trihydrate; atorvastatin calcium trihydrate; 344423-98-9; Atorvastatin hemicalcium trihydrate; Totalip; Atorvastatin calcium salt trihydrate; ATORVASTATIN CALCIUM; Torvast; Atorvastatin calcium [USAN]; atorvastatin calcium salt
|
| HS Tariff Code |
2934.99.9001
|
| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
|
|---|---|
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 0.8269 mL | 4.1343 mL | 8.2686 mL | |
| 5 mM | 0.1654 mL | 0.8269 mL | 1.6537 mL | |
| 10 mM | 0.0827 mL | 0.4134 mL | 0.8269 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
