HMG-CoA reductase; HMG-CoA/3-hydroxy-3-methylglutaryl coenzyme A
Atorvastatin targets HMG-CoA reductase (3-hydroxy-3-methylglutaryl-CoA reductase), the rate-limiting enzyme in the cholesterol biosynthesis pathway. HMG-CoA reductase catalyzes the conversion of HMG-CoA to mevalonate, a key step in cholesterol synthesis. By competitively inhibiting this enzyme, atorvastatin reduces de novo cholesterol synthesis, leading to decreased intracellular cholesterol levels. This results in increased expression of LDL receptors on the cell surface, enhancing the clearance of LDL-cholesterol from the bloodstream.

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].
In vitro, atorvastatin acts as a potent competitive inhibitor of HMG-CoA reductase. Its activity is confirmed through enzyme inhibition assays measuring the conversion of HMG-CoA to mevalonate. The compound's lipid-lowering effects are well-established through extensive research. Detailed IC₅₀ values for HMG-CoA reductase inhibition are not extensively reported in the available literature, but the compound's potency is well-characterized.

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].

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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]
In vivo, atorvastatin is used clinically for lowering blood cholesterol and for the prevention of cardiovascular disease events. It reduces serum levels of LDL-cholesterol and triglycerides while increasing HDL-cholesterol. The compound's in vivo efficacy is well-established through extensive clinical use, including large-scale outcome trials demonstrating reduced cardiovascular morbidity and mortality.

Non-cell-based enzyme assays for atorvastatin typically involve HMG-CoA reductase inhibition assays using purified HMG-CoA reductase enzyme. The compound is incubated with the enzyme, its substrate HMG-CoA, and NADPH at varying concentrations. HMG-CoA reductase activity is measured by quantifying the conversion of HMG-CoA to mevalonate using spectrophotometric, radiometric, or HPLC methods. IC₅₀ values for enzyme inhibition are determined from dose-response curves.

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].
Cellular assays for atorvastatin are performed using hepatocytes or other cells to assess effects on cholesterol synthesis and LDL receptor expression. Cells are treated with the compound at various concentrations, and cholesterol synthesis is measured using radiolabeled acetate or other precursors. LDL receptor expression is measured by flow cytometry or Western blotting. The compound's effects on cell proliferation and apoptosis may also be assessed.

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.
In vivo animal models for atorvastatin include studies in hypercholesterolemic animal models, such as rabbits or hamsters fed a high-cholesterol diet. The compound is administered orally at various doses. Serum lipid levels (total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides) are measured. Atherosclerosis progression is assessed by histological analysis of aortas. These studies confirm the compound's lipid-lowering and anti-atherosclerotic effects.

Atorvastatin exhibits dose-dependent and non-linear pharmacokinetic characteristics. It is rapidly absorbed after oral administration. Following a 40 mg dose, peak plasma concentrations of 28 ng/ml are reached within 1–2 hours, with an AUC of approximately 200 ng∙h/ml. Atorvastatin undergoes extensive first-pass metabolism in the intestinal wall and liver, resulting in an absolute oral bioavailability of only 14%. Plasma atorvastatin concentrations are lower after evening administration compared to morning administration (Cmax and AUC are reduced by approximately 30%). However, the reduction in LDL-C is the same regardless of when the medication is taken. Concomitant administration with food leads to prolonged Tmax and decreased Cmax and AUC. Breast cancer resistance protein (BCRP), a membrane-bound protein, plays a crucial role in the absorption of atorvastatin. Pharmacological and genetic studies have shown that the BCRP gene c.421C>A single nucleotide polymorphism (SNP) is associated with the BCRP gene 421AA genotype. Individuals carrying the 421AA genotype have reduced functional activity, and the AUC value of atorvastatin is 1.72 times higher than that of controls carrying the 421CC genotype. This is significant for individual differences in drug efficacy and toxicity, and it is particularly noteworthy that the incidence of the BCRP c.421C>A polymorphism is higher in Asian populations than in Caucasians. Other statins affected by this polymorphism include fluvastatin, simvastatin, and rosuvastatin. Genetic differences in the liver transport protein OATP1B1 (organic anion transport polypeptide 1B1), encoded by the SCLCO1B1 gene (a member of the solute carrier organic anion transporter family 1B1), have been shown to affect the pharmacokinetics of atorvastatin. Pharmacological studies of the c.521T>C single nucleotide polymorphism (SNP) in the gene encoding OATP1B1 (SLCO1B1) showed that the atorvastatin AUC was 2.45-fold higher in homozygous individuals of 521CC compared to those of 521TT. Other statins affected by this polymorphism include simvastatin, pitavastatin, rosuvastatin, and pravastatin.
Elimination Pathway
Atorvastatin and its metabolites are primarily excreted via bile and do not undergo enterohepatic circulation. Renal clearance of atorvastatin is extremely low, less than 1% of the eliminated dose.
Volume of Distribution
The volume of distribution of atorvastatin has been reported to be 380 liters.
Clearance
The recorded total plasma clearance of atorvastatin is 625 mL/min.
/Breast Milk/ In another experiment, female Wistar rats were given a single dose of 10 mg/kg atorvastatin on day 19 of gestation or day 13 of lactation, respectively. Results showed that the drug was transplacental and excreted into breast milk. PMID: 9520344
Lipitor and its metabolites are primarily metabolized in the liver and/or extrahepatically and excreted via bile; however, the drug does not appear to undergo enterohepatic circulation. Less than 2% of the dose is recovered in the urine after oral administration of Lipitor.
/Breast Milk/ It is unclear whether atorvastatin is excreted into human breast milk, but small amounts of similar drugs do enter breast milk. The drug concentrations in the plasma and liver of lactating rat pups were 50% and 40% of the concentrations in their breast milk, respectively.
The mean volume of distribution of Lipitor is approximately 381 liters. Lipitor binds to plasma proteins ≥98%. The blood/plasma ratio is approximately 0.25, indicating poor erythrocyte penetration.
For more complete data on the absorption, distribution, and excretion of atorvastatin (8 items), please visit the HSDB records page.

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Metabolism/Metabolites
Atorvastatin is primarily metabolized by cytochrome P450 3A4 in the intestine and liver to ortho- and para-hydroxylated derivatives and various β-oxidation products. Atorvastatin metabolites are further lactonized by the enzymes UGT1A1 and UGT1A3 through the formation of acylglucuronide intermediates. These lactones can be hydrolyzed back to their corresponding acidic forms and are in equilibrium. In vitro studies have shown that the ortho- and para-hydroxylated metabolites have inhibitory effects on HMG-CoA reductase comparable to atorvastatin. Approximately 70% of circulating HMG-CoA reductase inhibitory activity is attributed to the active metabolite. Lipitor is extensively metabolized into ortho- and para-hydroxylated derivatives and various β-oxidation products. In vitro studies have shown that the ortho- and para-hydroxylated metabolites have inhibitory effects on 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase comparable to atorvastatin. Approximately 70% of circulating HMG-CoA reductase inhibitory activity is attributed to the active metabolite. In vitro studies have demonstrated the importance of atorvastatin's metabolism via cytochrome P450 3A4, consistent with the increased plasma concentrations of atorvastatin in humans after co-administration with erythromycin, a known inhibitor of this isoenzyme. In animals, the ortho-hydroxy metabolite undergoes further glucuronidation.
All commercially available hydroxymethylglutaryl-CoA (HMG) reductase inhibitors share a common dihydroxyheptanoic acid or heptenic acid side chain in their active forms. This study provides evidence of the formation of acyl glucuronide conjugates of the hydroxy acid forms of simvastatin (SVA), atorvastatin (AVA), and cerivastatin (CVA) in rat, dog, and human liver formulations in vitro, and confirms the excretion of SVA acyl glucuronides in canine bile and urine. Two major products were detected after incubation of each statin (SVA, CVA, or AVA) with liver microsomal formulations supplemented with UDP-glucuronic acid. Based on high-performance liquid chromatography, ultraviolet spectroscopy, and/or liquid chromatography-mass spectrometry analysis, these metabolites were identified as statin hydroxy acid glucuronide conjugates and their corresponding δ-lactones. The structure of glucuronide was determined to be a 1-O-acyl-β-D-glucuronide conjugate of statin acid using liquid chromatography-nuclear magnetic resonance (LC-NMR). In human liver microsomes, the formation of statin glucuronide and statin lactone showed small inter-individual differences (3–6-fold; n = 10). Studies using expressed UDP glucuronyltransferase (UGT) showed that both UGT1A1 and UGT1A3 could generate glucuronide conjugates of all three statins and their corresponding lactones. Kinetic studies of statin glucuronidation and lactone formation in liver microsomes revealed significant species differences in the intrinsic clearance rate (CL(int)) of SVA (but not AVA or CVA), with dogs exhibiting the highest CL(int), followed by rats and humans. Among the statins studied, SVA exhibited the lowest clearance (CL(int)) in human liver microsomes due to glucuronidation and lactone formation (0.4 μL/min/mg protein for SVA, compared to approximately 3 μL/min/mg protein for AVA and CVA). Consistent with current in vitro findings, significant amounts of SVA glucuronide conjugates (approximately 20% of the dose) and lactone forms of SVA [simvastatin (SV); approximately 10% of the dose] were detected in bile after intravenous administration of [(14)C]SVA in dogs. SVA acylglucuronide conjugates isolated from in vitro incubation spontaneously cyclized to SV. Given the high rate of this lactone formation at physiological pH conditions, the current findings suggest that statin lactones previously detected in bile and/or plasma after animal administration of SVA or animal and human administration of AVA or CVA may be at least partially derived from the corresponding acylglucuronide conjugates. Therefore, the formation of acyl glucuronide appears to be a common metabolic pathway for the hydroxy acid form of statins, and may play an important, though previously unrecognized, role in the conversion of active HMG-CoA reductase inhibitors to their potential δ-lactone forms. PMID:11950779 Prueksaritanont T et al.; Drug Metab Dispos 30 (5): 505-12 (2002)
This study evaluated the genetic variations associated with the pharmacokinetics of atorvastatin (ATV) in a Mexican population. The aim of this study was to: 1) reveal the frequency of 87 polymorphisms in 36 genes associated with drug metabolism in healthy Mexican volunteers; 2) assess the impact of these polymorphisms on the pharmacokinetics of atorvastatin (ATV); 3) classify the ATV metabolic phenotype in healthy volunteers; and 4) explore the possible association between genotype and metabolic phenotype. This study conducted a pharmacokinetic study of ATV (80 mg single dose) in 60 healthy male volunteers. Plasma concentrations of atazanavir (ATV) were determined using high-performance liquid chromatography-mass spectrometry (HPLC-MS/MS). Pharmacokinetic parameters were calculated using a non-compartmental model. Polymorphisms were detected using PHARMA chip microarray and TaqMan probe genotyping. Three metabolic phenotypes were identified in the study population: slow metabolizer, normal metabolizer, and rapid metabolizer. Six gene polymorphisms were found to significantly affect the pharmacokinetics of atazanavir (ATV): MTHFR (rs1801133), DRD3 (rs6280), GSTM3 (rs1799735), TNFα (rs1800629), MDR1 (rs1045642), and SLCO1B1 (rs4149056). The combination of MTHFR, DRD3, and MDR1 polymorphisms was associated with a slow ATV metabolism phenotype. PMID: 26857559 Full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4746878 Leon-Cachon RB et al.; BMC Cancer 16: 74 (2016)
The known metabolites of atorvastatin include 7-[2-(4-fluorophenyl)-4-[(2-hydroxyphenyl)carbamoyl]-3-phenyl-5-propyl-2-ylpyrrolo-1-yl]-3,5-dihydroxyheptanoic acid and 7-[2-(4-fluorophenyl)-4-[(4-hydroxyphenyl)carbamoyl]-3-phenyl-5-propyl-2-ylpyrrolo-1-yl]-3,5-dihydroxyheptanoic acid. S73 | METXBIODB | Metabolite Response Database from BioTransformer | DOI:10.5281/zenodo.4056560NORMAN Suspicious List Exchange Atorvastatin is extensively metabolized to ortho- and para-hydroxylated derivatives and various β-oxidation products. The ortho- and para-hydroxylated metabolites exhibit comparable in vitro inhibitory activity against HMG-CoA reductase to atorvastatin. Approximately 70% of circulating HMG-CoA reductase inhibitory activity is attributed to the active metabolite. CYP3A4 is also involved in the metabolism of atorvastatin.

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Biological Half-Life
Atorvastatin has a half-life of 14 hours, while its metabolites have half-lives up to 30 hours.
/Milk/...After administration to lactating rats, the radioactivity in their milk reached a maximum of 17.1 ng equivalents/mL at 6.0 hours, then decreased over a half-life of 7.8 hours. Nemoto H et al.; Pharmacology and Medicine 26(7): 79-96 (1998)
The average plasma elimination half-life of Lipitor in humans is about 14 hours, but due to the contribution of its active metabolites, its inhibitory activity half-life against HMG-CoA reductase is 20 to 30 hours.
Atorvastatin calcium trihydrate has a molecular weight of 1209.41 g/mol and a molecular formula of C₆₆H₆₈CaF₂N₄O₁₀·3H₂O. CAS number is 344423-98-9. Purity is typically ≥97%. Storage conditions: powder at -20°C. The compound is supplied for research use only. Detailed PK parameters such as half-life and bioavailability are well-established from clinical use.

Toxicity Overview
Identification and Use: Atorvastatin is a cholesterol-lowering drug and an inhibitor of hydroxymethylglutaryl-CoA reductase. Human Exposure and Toxicity: Rare cases of fatal and non-fatal hepatic failure have been reported in patients taking statins, including atorvastatin. Rare cases of rhabdomyolysis and acute renal failure due to myoglobinuria have also been reported in patients taking statins, including atorvastatin. Since cholesterol and its derivatives are essential for normal fetal development, lipid-lowering drugs offer no benefit during pregnancy. Atherosclerosis is a chronic process, and discontinuation of lipid-lowering drugs during pregnancy has minimal impact on the long-term efficacy of treatment for primary hypercholesterolemia. Neuropsychiatric reactions are associated with statin therapy. These reactions include behavioral changes, cognitive and memory impairments, sleep disturbances, and sexual dysfunction. Animal studies: In a two-year rat carcinogenicity study, two rare tumors were found in the muscles of female rats in the high-dose group at doses of 10, 30, and 100 mg/kg/day: one was rhabdomyosarcoma and the other was fibrosarcoma. In dogs treated with 10, 40, or 120 mg/kg for two years, atorvastatin did not have adverse effects on semen parameters or reproductive organ histopathology. In male rats treated with 100 mg/kg/day 11 weeks before mating, sperm motility and sperm head concentration were decreased, and the number of abnormal sperm was increased. Studies in rats at doses up to 175 mg/kg showed that atorvastatin had no effect on fertility. Ten rats were treated with atorvastatin at 100 mg/kg/day for three consecutive months. Two of them developed epididymal hypoplasia and azoospermia. Testicular weight was significantly reduced in the 30 mg/kg and 100 mg/kg dose groups, with the 100 mg/kg dose group also showing lower epididymal weight. In another study, rats were administered atorvastatin at doses of 20, 100, or 225 mg/kg/day from day 7 of gestation to day 21 of lactation (weaning). The results showed that pups born to mothers in the 225 mg/kg/day dose group had reduced survival rates at birth, during the neonatal period, at weaning, and at maturity. Pups born to mothers in the 100 mg/kg/day dose group showed weight loss on days 4 and 21 after birth; pups born to mothers in the 225 mg/kg/day dose group showed weight loss at birth and on days 4, 21, and 91 after birth. The pups exhibited developmental delays. In vitro studies showed that atorvastatin did not exhibit mutagenicity or chromosomal breakage in the following tests, regardless of metabolic activation: Ames test for Salmonella and Escherichia coli, HGPRT positive mutation test in Chinese hamster lung cells, and chromosomal aberration test in Chinese hamster lung cells. In vivo mouse micronucleus assays were also negative. Atorvastatin selectively and competitively inhibits the hepatic enzyme HMG-CoA reductase. Since HMG-CoA reductase is responsible for converting HMG-CoA to mevalonate in the cholesterol biosynthesis pathway, inhibition of HMG-CoA reductase leads to a decrease in hepatic cholesterol levels. Decreased hepatic cholesterol levels stimulate upregulation of hepatic low-density lipoprotein cholesterol (LDL-C) receptors, thereby increasing hepatic LDL-C uptake and reducing serum LDL-C concentration.

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Hepatotoxicity
Atorvastatin treatment is associated with mild, asymptomatic, and usually transient elevations in serum transaminases in 1% to 3% of patients, but less than 1% of patients experience ALT levels exceeding 3 times the upper limit of normal (ULN). In a pooled analysis of large-scale prospective surveillance studies, the proportion of patients receiving atorvastatin with ALT levels exceeding 3 times the ULN was 0.7%, compared to 0.3% in the placebo group. These elevations are more common with high-dose atorvastatin treatment, with an incidence of 2.3% in the 80 mg daily dose group. Most elevations are self-limiting and do not require dose adjustment.
Atorvastatin is also associated with significant, clinically observable liver injury, but this is rare, occurring in approximately 1/3000 to 1/5000 of treated patients. The clinical presentation of atorvastatin hepatotoxicity varies widely, ranging from simple cholestatic hepatitis to mixed types and significant hepatocellular damage. The latency period for the onset of injury also varies considerably, ranging from 1 month to several years. However, most cases occur within 6 months of starting atorvastatin or within months of dose escalation. The most common presentation is cholestatic hepatitis, which is usually mild to moderate in severity and self-limiting (cases 1 and 2). Atorvastatin hepatotoxicity can also present as a marked pattern of hepatocellular damage, with significantly elevated serum transaminase levels and little or no elevation in alkaline phosphatase levels. Rash, fever, and eosinophilia are uncommon, but at least one-third of hepatocellular carcinoma cases have autoimmune features, including elevated immunoglobulin levels, positive antinuclear antibodies (ANA), and liver biopsy confirming autoimmune hepatitis (cases 3 and 4). These autoimmune cases usually resolve upon discontinuation of atorvastatin, but sometimes glucocorticoid therapy may be required for complete recovery. Notably, however, some suspected autoimmune hepatitis cases caused by atorvastatin do not resolve after discontinuation but persist, requiring long-term immunosuppressive therapy. It is currently unclear whether these cases of persistent autoimmune hepatitis are caused by statin treatment or induced by statin use in susceptible hosts. Another possibility is that this association is purely coincidental and represents new-onset autoimmune hepatitis in people taking statins.
Probability rating: A (Known cause of clinically significant liver damage).

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Impact during pregnancy and lactation
◉ Overview of medication use during lactation
It is generally believed that women taking statins should not breastfeed due to concerns about disrupting the infant's lipid metabolism. However, some argue that children with homozygous familial hypercholesterolemia who start taking statins from age 1 have low oral bioavailability and therefore pose a lower risk to breastfed infants, especially rosuvastatin and pravastatin. Some evidence suggests that infants of breastfeeding mothers taking atorvastatin did not experience significant developmental problems. Until more data is available, especially regarding newborns or premature infants, alternative medications may be preferred.
◉ Impact on Breastfed Infants
In a case series of patients with homozygous familial hypercholesterolemia, six patients breastfed a total of 11 infants after restarting statin therapy postpartum. The study did not report the specific statins used by these women, but most women taking statins used atorvastatin at 40 or 80 mg daily. All infants had normal early development. All children started school on time, and no learning difficulties were reported.
◉ Effects on Lactation and Breast Milk
Gynecomastia has been reported in men taking atorvastatin. In one case, serum prolactin levels were normal. In another case, suspected rosuvastatin-induced gynecomastia resolved after the patient switched to atorvastatin.

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Protein Binding
Atorvastatin is highly bound to plasma proteins, with over 98% of the administered dose present in bound form.
Atorvastatin has a well-established safety profile from its extensive clinical use. Common side effects include myalgia, elevated liver enzymes, and gastrointestinal disturbances. The compound is for research use only in the context of this request and is not for human consumption in a research setting. Standard laboratory safety precautions should be followed when handling the compound.

[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.

Atorvastatin calcium trihydrate is the trihydrate form of atorvastatin calcium. It is an environmental pollutant and an exogenous substance. It is a hydrate and also a synthetic statin drug. It contains atorvastatin calcium. Atorvastatin calcium is the calcium salt of atorvastatin, a synthetic lipid-lowering drug. Atorvastatin competitively inhibits hepatic hydroxymethylglutaryl-CoA (HMG-CoA) reductase, which catalyzes the conversion of HMG-CoA to mevalonate, a key step in cholesterol synthesis. This drug increases the number of low-density lipoprotein (LDL) receptors on the surface of hepatocytes, enhances LDL uptake and catabolism, reduces LDL production and the number of LDL particles, and lowers plasma cholesterol and lipoprotein levels. Like other statins, atorvastatin may also have direct antitumor activity, possibly through the inhibition of farnesylation and geranylation of proteins such as small GTP-binding proteins, leading to cell cycle arrest in the G1 phase. This drug may also enhance the sensitivity of tumor cells to cell inhibitors by inhibiting Akt phosphorylation in a mTOR-dependent manner. Atorvastatin is a pyrrole and heptanoic acid derivative, belonging to the class of hydroxymethylglutaryl-CoA reductase inhibitors (statins), and is also a cholesterol-lowering drug used to reduce serum low-density lipoprotein cholesterol, apolipoprotein B, and triglyceride levels. This product is used to treat hyperlipidemia, increase serum high-density lipoprotein cholesterol (HDL-C) levels, and prevent cardiovascular disease in patients with multiple risk factors. See also: Atorvastatin (containing the active ingredient); Atorvastatin calcium trihydrate; Ezetimibe (one of the components).

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Drug Indications
Simple hypercholesterolemia (heterozygous, homozygous, or other primary hypercholesterolemia), mixed hyperlipidemia; prevention of cardiovascular events.

Atorvastatin calcium trihydrate is the calcium salt trihydrate form of atorvastatin, a competitive inhibitor of HMG-CoA reductase. It is a lipid-lowering agent used in the treatment of cardiovascular diseases. The compound reduces serum LDL-cholesterol levels and is used for the prevention of cardiovascular events. Atorvastatin is a pyrrole and heptanoic acid derivative. It is used in research applications studying cholesterol metabolism and cardiovascular disease. It is for research use only.

C66H74CAF2N4O13

1209.3876

1208.484

C, 65.55; H, 6.17; Ca, 3.31; F, 3.14; N, 4.63; O, 17.20

344423-98-9

134523-03-8 (calcium);344423-98-9 (calcium trihydrate);134523-00-5 (free acid);134523-01-6 (sodium); 874114-41-7 (magnesium);

656846

Typically exists as White to off-white solid at room temperature

9.91

9

15

22

86

817

4

[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]

SHZPNDRIDUBNMH-NIJVSVLQSA-L

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

calcium (3R,5R)-7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoate trihydrate

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

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

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

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.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*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).

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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)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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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).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)