HMG-CoA reductase

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].

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]

The HMG-CoA reductase assay kit with the catalytic domain of the human enzyme (recombinant GST fusion protein expressed in E. coli) was used, under conditions recommended by the manufacturer, to identify the most effective fraction of plant extract. The concentration of the purified human enzyme stock solution was 0.52–0.85 mg protein/mL. Reference statin drug pravastatin was used as positive control. To characterize HMG-CoA reductase inhibition under defined assay conditions, reactions containing 4 μL of NADPH (to obtain a final concentration of 400 μM) and 12 μL of HMG-CoA substrate (to obtain a final concentration of 400 μM) in a final volume of 0.2 mL of 100 mM potassium phosphate buffer, pH 7.4 (containing 120 mM KCl, 1 mM EDTA, and 5 mM DTT), were initiated (time 0) by the addition of 2 μL of the catalytic domain of human recombinant HMG-CoA reductase and incubated in Eppendorf BioSpectrometer (equipped with thermostatically controlled cell holder) at 37°C in the presence or absence (control) of 1 μL aliquots of drugs dissolved in DMSO. The rates of NADPH consumed were monitored every 20 sec for up to 15 min by scanning spectrophotometrically [7].

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/Disease Models: 40 8weeks old ApoE−/− mice, angiotensin II (Ang II) induced [5]
Doses: 20 mg/kg, 30 mg/kg
Route of Administration: po (oral gavage); one time/day; continuous 28-day
Experimental Results: Endoplasmic reticulum stress signaling proteins, the number of apoptotic cells, and the activation of Caspase12 and Bax were Dramatically diminished in Ang II-induced ApoE−/− mice. Pro-inflammatory cytokines such as IL-6, IL-8, and IL-1β were Dramatically inhibited.

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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.

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Effect of atorvastatin on hypernociception induced by bradykinin, cytokines or PGE2 [1]
In this set of experiments, the effect of atorvastatin was investigated on mechanical hypernociception induced by bradykinin (BK) (500 ng paw−1), TNF-α (50 pg paw−1), IL-1β (1 ng paw−1), keratinocyte-derived chemokine (KC/CXCL) (20 ng paw−1) and PGE2 (100 ng paw−1). The animals were pretreated for 3 days with atorvastatin (30 mg kg−1, peritoneally (p.o.)) or PBS, as described above. Hypernociception was assessed 3 h after injection of the inflammatory stimulus (or saline) in the paw.

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Effect of atorvastatin on IL-1β and PGE2 production induced by LPS [1]
To investigate whether the antinociceptive effect of atorvastatin depended on the inhibition of IL-1β and PGE2 production induced by LPS, the levels of these mediators were measured in the paw skin of mice pretreated for 3 days with atorvastatin (30 mg kg−1 p.o.) or PBS, as described above. The levels of these mediators in paw skin were determined 3 h after injection of LPS or saline into the paw.

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Influence of NOS inhibitors on the antinociceptive effect of atorvastatin [1]
To assess the contribution of NO to the antinociceptive effect of atorvastatin, animals were pretreated with the statin, as described above. One hour before the injection of LPS or PGE2 into the paw, mice received an NOS inhibitor, either l-arginine analog N-nitro-l-arginine methyl ester (l-NAME) (90 mg kg−1, i.p.), L-NMMA (90 mg kg−1, i.p.) or 1400W (1.5 mg kg−1, i.v.). In a different series of experiments, using the mice lacking iNOS (iNOS −/−) and the relevant WT mice, we assessed the effect of atorvastatin (given as described) on LPS-induced hypernociception. In both sets of experiments, hypernociception was assessed 3 h after injection of LPS- or PGE2-i.pl.

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Role of products of HMG-CoA reductase on the antinociceptive effect of atorvastatin [1]
To investigate whether the antinociceptive effect of atorvastatin reflected decreased levels of the products of HMG-CoA, two types of experiments were performed. In one, the total serum cholesterol concentration was determined in mice treated with atorvastatin at a dose of 30 mg kg−1 day−1, or PBS, for 3 days and then injected i.pl. with LPS or saline. In the other, the HMG-CoA reductase product, mevalonate, was given (10–90 mg kg−1) at the same times as atorvastatin. Hypernociception and cholesterol levels were determined 3 h after i.pl. LPS or saline.

Absorption, Distribution and Excretion
Atorvastatin exhibits dose-dependent and non-linear pharmacokinetic characteristics. It is rapidly absorbed after oral administration. Peak plasma concentrations of 28 ng/ml are reached within 1–2 hours after a 40 mg dose, 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 (Cmax and AUC are reduced by approximately 30%) compared to morning administration. However, the reduction in LDL-C is the same regardless of when the medication is taken. Co-administration with food leads to prolonged Tmax and decreased Cmax and AUC. Breast cancer resistance protein (BCRP) is a membrane-bound protein that plays an important role in the absorption of atorvastatin. Pharmacogenetic studies have shown an association between the c.421C>A single nucleotide polymorphism (SNP) in the BCRP gene and the BCRP genotype c.421C>A. Individuals carrying the 421AA genotype exhibit reduced functional activity of atorvastatin, with an AUC value 1.72 times higher than that of the control group carrying the 421CC genotype. This is significant for individual differences in drug efficacy and toxicity, notably, the BCRP c.421C>A polymorphism is more prevalent 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. Pharmacogenetic 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 homozygotes. Other statins affected by this polymorphism include simvastatin, pitavastatin, rosuvastatin, and pravastatin. Atorvastatin and its metabolites are primarily excreted via bile and do not undergo enterohepatic circulation. Renal excretion of atorvastatin is minimal, less than 1% of the excreted dose. The reported volume of distribution of atorvastatin is 380 liters. 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. The results showed that the drug was transplacental and excreted into breast milk.
Lipitor and its metabolites are primarily metabolized in the liver and/or extrahepaticly 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 secreted 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 record 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 to form 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 comparable inhibitory effects on HMG-CoA reductase as atorvastatin. Approximately 70% of circulating HMG-CoA reductase inhibitory activity is attributed to the active metabolite.
Lipitor is extensively metabolized to ortho- and para-hydroxylated derivatives and various β-oxidation products. The ortho- and para-hydroxylated metabolites exhibit in vitro inhibitory activity against 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase comparable to that of Lipitor. Approximately 70% of the circulating HMG-CoA reductase inhibitory activity is attributed to the active metabolite. In vitro studies have shown that cytochrome P450 3A4 is crucial for the metabolism of Lipitor, consistent with the increased plasma concentrations of Lipitor 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-CoA) 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 in vitro rat, dog, and human liver formulations, as well as evidence of the excretion of SVA acyl glucuronide 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 glucuronide conjugates of the hydroxy acid forms of statins and their corresponding δ-lactones. The structure of this glucuronide was confirmed by liquid chromatography-nuclear magnetic resonance (LC-NMR) as a 1-O-acyl-β-D-glucuronide conjugate of statin acid. The production of statin glucuronide and statin lactone in human liver microsomes showed relatively 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 and their corresponding lactones for all three statin classes. 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 underwent glucuronidation and lactone formation in human liver microsomes, exhibiting the lowest CL(int) (SVA: 0.4 μL/min/mg protein, 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 [simvastatin (SV); approximately 10% of the dose] were detected in bile following intravenous administration of [(14)C]SVA. The SVA acylglucuronide conjugates isolated from in vitro incubation spontaneously cyclized to SV. Given the high rate of this lactone formation under physiological pH conditions, these results suggest that statin lactones previously detected in bile and/or plasma following SVA administration in animals or AVA or CVA administration in animals and humans may be at least partially derived from the corresponding acylglucuronide conjugates. Therefore, the formation of acylglucuronides appears to be a common metabolic pathway for the hydroxy acid forms of statins, potentially playing an important, though previously unrecognized, role in the conversion of active HMG-CoA reductase inhibitors to their potential δ-lactone forms.
Genetic variations related to the pharmacokinetics of atorvastatin (ATV) were evaluated in a Mexican population. This study aimed to: 1) reveal the frequencies of 87 polymorphisms in 36 genes related to drug metabolism in healthy Mexican volunteers; 2) assess the impact of these polymorphisms on the pharmacokinetics of atorvastatin (ATV); 3) classify the ATV metabolic phenotypes in healthy volunteers; and 4) explore potential associations between genotype and metabolic phenotype. This study conducted a pharmacokinetic study of ATV (a single 80 mg dose) in 60 healthy male volunteers. Plasma concentrations of 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 fast metabolizer. The study found that six gene polymorphisms significantly affected the pharmacokinetics of atorvastatin (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 phenotype of slow metabolism of atorvastatin (ATV). Atorvastatin's known metabolites include 7-[2-(4-fluorophenyl)-4-[(4-hydroxyphenyl)carbamoyl]-3-phenyl-5-propyl-2-ylpyrrolo-1-yl]-3,5-dihydroxyheptanoic acid and 7-[2-(4-fluorophenyl)-4-[(2-hydroxyphenyl)carbamoyl]-3-phenyl-5-propyl-2-ylpyrrolo-1-yl]-3,5-dihydroxyheptanoic acid. Atorvastatin is extensively metabolized to ortho- and para-hydroxylated derivatives and various β-oxidation products. In vitro studies have shown that the ortho- and para-hydroxylated metabolites have comparable inhibitory effects on 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 a half-life of 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.
Lipitor has a mean plasma elimination half-life of approximately 14 hours in humans, but due to the contribution of its active metabolites, its inhibitory activity against HMG-CoA reductase has a half-life of 20 to 30 hours.

Toxicity Summary
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, there is no benefit to lipid-lowering drugs 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. Neurological and psychiatric reactions are associated with statin treatment. 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 administered 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 administered 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 in vitro studies, 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 test results were 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, it leads to a decrease in hepatic cholesterol levels. This decrease in hepatic cholesterol levels stimulates the upregulation of hepatic LDL-C receptors, thereby increasing hepatic LDL-C uptake and reducing serum LDL-C concentrations. Toxicity Data: Overall, the condition was well tolerated. Side effects may include myalgia, constipation, fatigue, abdominal pain, and nausea. Other possible side effects include myotoxicity (myopathy, myositis, rhabdomyolysis) and hepatotoxicity. To avoid toxicity in Asian patients, dose reduction should be considered.
Drug Interactions
Atorvastatin co-administration with efavirenz may result in decreased plasma concentrations of atorvastatin.
When atorvastatin (10 mg daily for 3 days) was co-administered with efavirenz (600 mg once daily for 14 days), the peak plasma concentration and AUC of atorvastatin decreased by 1% and 41%, respectively. When atorvastatin (80 mg once daily for 14 days) was co-administered with digoxin (0.25 mg once daily for 20 days), the peak plasma concentration and AUC of digoxin increased by 20% and 15%, respectively. Therefore, patients receiving such combination therapy should be appropriately monitored.
Atorvastatin co-administration with azole antifungals (e.g., itraconazole) increases the risk of myopathy or rhabdomyolysis. When atorvastatin (40 mg single dose) is co-administered with itraconazole (200 mg once daily for 4 days), the peak plasma concentration and area under the plasma concentration-time curve (AUC) of atorvastatin increase by 20% and 3.3 times, respectively. Clinicians should weigh the benefits and risks of this combination therapy when considering atorvastatin with itraconazole or other azole antifungals. During co-treatment with itraconazole, the lowest effective dose of atorvastatin should be used, and the daily dose of atorvastatin should not exceed 20 mg. Patients receiving co-treatment with atorvastatin and azole antifungals should be monitored for symptoms such as muscle pain, tenderness, or weakness, especially at the beginning of treatment and after escalation of either drug.
Co-administration of atorvastatin with cyclosporine increases the risk of myopathy or rhabdomyolysis. When atorvastatin (10 mg daily for 28 days) was used in combination with cyclosporine (5.2 mg/kg daily), the peak plasma concentration and AUC of atorvastatin increased by 10.7-fold and 8.7-fold, respectively. Concomitant use of atorvastatin and cyclosporine should be avoided. For more complete data on drug interactions of atorvastatin (out of 27), please visit the HSDB record page.

[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.

Therapeutic Uses

Cholesterol-lowering drug; hydroxymethylglutaryl-CoA reductase inhibitor
For adult patients with asymptomatic coronary artery disease (CAD) but with multiple CAD risk factors (e.g., age, smoking, hypertension, low HDL cholesterol, or a family history of early-onset CAD), Lipitor is indicated for: reducing the risk of myocardial infarction; reducing the risk of stroke; reducing the risk of revascularization surgery and angina. /US product label includes/
For patients with type 2 diabetes and asymptomatic CAD but with multiple CAD risk factors (e.g., retinopathy, proteinuria, smoking, or hypertension), Lipitor is indicated for: reducing the risk of myocardial infarction; reducing the risk of stroke. /US product label includes/
For patients with clinically diagnosed CAD, Lipitor is indicated for: reducing the risk of non-fatal myocardial infarction; reducing the risk of fatal and non-fatal stroke; reducing the risk of revascularization surgery; reducing the risk of hospitalization for congestive heart failure (CHF); reducing the risk of angina. /US Product Label Contains/
For more complete data on the therapeutic uses of atorvastatin (of 15), please visit the HSDB record page.

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Drug Warnings
Lipitor is contraindicated in women who are pregnant or may become pregnant. Serum cholesterol and triglyceride levels are elevated during normal pregnancy. Lipid-lowering drugs are ineffective during pregnancy because the fetus requires cholesterol and its derivatives for normal development. Atherosclerosis is a chronic process, and discontinuing lipid-lowering drugs during pregnancy has little effect on the long-term treatment of primary hypercholesterolemia.
Statins may harm the fetus when taken by pregnant women. Lipitor should only be used by women of childbearing potential if pregnancy is extremely unlikely and the potential risks have been explained. If a woman becomes pregnant while taking Lipitor, she should discontinue the drug immediately and be informed again of the potential harm to the fetus and the lack of known clinical benefit of continuing the drug during pregnancy.
It is not known whether atorvastatin is excreted into human breast milk, but another drug in the same class is excreted in small amounts into breast milk. In lactating mice, plasma and liver drug concentrations were 50% and 40% of those in their mother's milk, respectively. Drug concentrations in animal milk may not accurately reflect those in human milk. Because another drug in the same class can enter breast milk, and statins can cause serious adverse reactions in nursing infants, women receiving Lipitor treatment should be advised against breastfeeding.
Myopathy (defined as muscle pain or weakness accompanied by creatine kinase [CK, creatine phosphokinase, CPK] concentrations exceeding the upper limit of normal [ULN] by 10 times has been occasionally reported in patients taking statins (including atorvastatin). Rhabdomyolysis with myoglobinuria leading to acute renal failure has also been reported occasionally in patients taking statins (including atorvastatin).
For more complete data on drug warnings for atorvastatin (33 in total), please visit the HSDB records page. Pharmacodynamics Atorvastatin is an oral lipid-lowering drug that reversibly inhibits HMG-CoA reductase. It lowers plasma concentrations of total cholesterol, low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (apo B), non-HDL-C, and triglycerides (TG), while increasing high-density lipoprotein cholesterol (HDL-C) concentrations. High LDL-C, low HDL-C, and high TG concentrations in plasma are associated with an increased risk of atherosclerosis and cardiovascular disease. The ratio of total cholesterol to HDL-C is a strong predictor of coronary artery disease, with a high ratio associated with a higher risk. Elevated HDL-C levels are associated with a reduced cardiovascular risk. Atorvastatin reduces the incidence and mortality of cardiovascular disease by lowering LDL-C and TG and increasing HDL-C. Elevated cholesterol levels, especially elevated low-density lipoprotein (LDL) levels, are a significant risk factor for cardiovascular disease. Clinical studies have shown that atorvastatin can reduce low-density lipoprotein cholesterol (LDL-C) and total cholesterol by 36-53%. In patients with β-lipoproteinemia, atorvastatin can reduce intermediate-density lipoprotein cholesterol levels. Furthermore, studies have shown that atorvastatin can limit angiogenesis, which may be helpful in treating chronic subdural hematoma. Myopathy/Rhabdomyolysis Like other HMG-CoA reductase inhibitors, atorvastatin carries a risk of drug-induced myopathy, characterized by muscle pain, tenderness, or weakness, accompanied by elevated creatine kinase (CK) levels. Myopathy often manifests as rhabdomyolysis, with or without myoglobinuria leading to acute renal failure. The risk of statin-induced myopathy is dose-related, and symptoms usually subside after discontinuation of the drug. Observational studies have indicated that 10-15% of patients taking statins may experience muscle soreness during treatment. Liver Dysfunction Statins, like some other lipid-lowering therapies, are associated with liver function biochemical abnormalities. In clinical trials, 0.7% of patients taking atorvastatin experienced persistently elevated serum transaminases (more than 3 times the upper limit of normal [ULN], occurring at least twice). This effect appears to be dose-related. Endocrine Effects Statins are associated with elevated serum glycated hemoglobin (HbA1c) and blood glucose levels. An in vitro study demonstrated dose-dependent cytotoxicity of human pancreatic β-cells after atorvastatin treatment. Furthermore, insulin secretion was decreased compared to the control group. HMG-CoA reductase inhibitors interfere with cholesterol synthesis and theoretically may interfere with adrenal and/or gonadal steroid production. Clinical studies of atorvastatin and other HMG-CoA reductase inhibitors have shown that these drugs do not affect plasma cortisol concentrations, basal plasma testosterone concentrations, or adrenal reserves. However, the effects of statins on male fertility have not been adequately investigated. The effects of statins on the pituitary-gonadal axis in premenopausal women are unclear. Cardiovascular System Significantly reduced circulating ubiquinone levels have been observed in patients treated with atorvastatin and other statins. The clinical significance of long-term statin use potentially leading to ubiquinone deficiency remains undetermined. There are reports that decreased myocardial ubiquinone levels may lead to impaired cardiac function in patients with borderline congestive heart failure. Lipoprotein A In some patients, the benefits of reduced total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels may be partially diminished by a concurrent increase in lipoprotein(a) (Lp(a)) concentration. Current knowledge suggests that high Lp(a) levels are an emerging risk factor for coronary artery disease. Further research indicates that the effect of statins on Lp(a) levels in patients with dyslipidemia depends on their apolipoprotein(a) phenotype; statins only increase Lp(a) levels in patients with a low molecular weight apolipoprotein(a) phenotype.

C33H35FN2O5

558.65

558.253

C, 70.95; H, 6.32; F, 3.40; N, 5.01; O, 14.32

134523-00-5

Atorvastatin hemicalcium salt;134523-03-8;(3S,5S)-Atorvastatin;501121-34-2;Atorvastatin-d5 hemicalcium;222412-82-0;(rel)-Atorvastatin;110862-48-1;Atorvastatin hemicalcium trihydrate;344920-08-7;Atorvastatin-d5 sodium;222412-87-5; 609843-23-4 (lysine); 344423-98-9 (calcium trihydrate); 1035609-19-8 (magnesium trihydrate); 134523-00-5 (free acid); 1072903-92-4 (strontium) ; 134523-01-6 (sodium); 874114-41-7 (magnesium);

60823

White to light yellow solid powder

1.2±0.1 g/cm3

722.2±60.0 °C at 760 mmHg

176-178°C

390.6±32.9 °C

0.0±2.5 mmHg at 25°C

1.603

4.13

4

6

12

41

822

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[H])O[H])O[H]

XUKUURHRXDUEBC-KAYWLYCHSA-N

InChI=1S/C33H35FN2O5/c1-21(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/h3-16,21,26-27,37-38H,17-20H2,1-2H3,(H,35,41)(H,39,40)/t26-,27-/m1/s1

(3R,5R)-7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoic acid

CI-981; CI981; Atorvastatin; liptonorm; Lipilou; Tozalip; Xavator; Lipitor; Cardyl; ATORVASTATIN CALCIUM; Torvast; Cardyl

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)

DMSO : ~50 mg/mL (~89.50 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (4.48 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (4.48 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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