HMG-CoA reductase; HMG-CoA/3-hydroxy-3-methylglutaryl coenzyme A
Selective inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (rate-limiting enzyme in cholesterol biosynthesis) with the following inhibitory parameter:
- IC50 = 8 nM (recombinant human HMG-CoA reductase); inhibits enzyme activity by >90% at 50 nM [3]

After myocardial infarction, atorvastatin treatment reduces myocardial cell apoptosis by downregulating the expression of GRP78, caspase-12, and CHOP in myocardial cells. Additionally, heart failure and angiotensin II (Ang II) stimulation trigger endoplasmic reticulum (ER) stress[4].

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Inhibition of human saphenous vein smooth muscle cell (HSVSMC) proliferation and invasion:
- In HSVSMCs (isolated from human saphenous veins), Atorvastatin Calcium (0.1–10 μM, 72-hour treatment) inhibited proliferation in a concentration-dependent manner:
- IC50 = 1.2 μM (MTT assay); 10 μM reduced cell viability by 70% vs. vehicle [2]
- Invasion inhibition: 10 μM Atorvastatin Calcium reduced HSVSMC invasion through Matrigel-coated Transwell inserts by 55% (crystal violet staining for migrated cells); downregulated matrix metalloproteinase-2 (MMP-2) protein by 45% (Western blot) [2]
- Suppression of inflammatory responses in macrophages:
- In LPS-stimulated RAW264.7 murine macrophages, Atorvastatin Calcium (1–20 μM, 24-hour treatment):
- 10 μM reduced TNF-α secretion by 60% and IL-1β secretion by 55% (ELISA);
- 20 μM inhibited nuclear translocation of NF-κB p65 by 70% (immunofluorescence staining) [1]
- Inhibition of myocardial cell apoptosis via downregulating endoplasmic reticulum (ER) stress:
- In H2O2-induced rat primary myocardial cells, Atorvastatin Calcium (5–20 μM, 24-hour treatment):
- 20 μM reduced apoptotic rate from 35% to 12% (Annexin V-FITC/PI flow cytometry);
- Downregulated ER stress markers: GRP78 protein by 50%, CHOP protein by 55%, and cleaved caspase-12 by 60% (Western blot) [4]
- Inhibition of ER stress in aortic smooth muscle cells (ASMCs):
- In TNF-α-stimulated human ASMCs (HASMCs), Atorvastatin Calcium (5–15 μM, 48-hour treatment):
- 15 μM reduced CHOP mRNA by 60% (qPCR) and cleaved caspase-3 by 50% (Western blot);
- Inhibited HASMC apoptosis by 45% (TUNEL assay) [5]

In the Ang II-induced ApoE-/- mice, atorvastatin (20–30 mg/kg; oral gavage; once daily; for 28 days; ApoE−/− mice) treatment dramatically reduces the amount of apoptotic cells, the activation of Caspase12 and Bax, and endoplasmic reticulum (ER) stress signaling proteins. After taking atorvastatin, proinflammatory cytokines like IL-6, IL-8, and IL-1β are all noticeably inhibited[5].

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Attenuation of inflammatory hypernociception in mice:
1. Animals: Male Swiss mice (25–30 g) were randomized into 4 groups (n=8/group): Vehicle, Atorvastatin Calcium 1 mg/kg, 5 mg/kg, 10 mg/kg [1]
2. Model induction: Inflammatory hypernociception was induced by intraplantar injection of carrageenan (1% in saline, 20 μL) into the right hind paw [1]
3. Treatment: Atorvastatin Calcium (dissolved in 0.5% CMC-Na) was administered via oral gavage 1 hour before carrageenan injection [1]
4. Results:
- Nociceptive threshold: 10 mg/kg group increased paw withdrawal threshold (von Frey test) by 65% vs. vehicle at 4 hours post-carrageenan;
- Spinal inflammation: 10 mg/kg reduced spinal TNF-α protein by 50% (Western blot) [1]
- Improvement of post-myocardial infarction (MI) heart failure in rats:
1. Animals: Male Wistar rats (250–300 g) were randomized into 3 groups (n=10/group): Sham, MI + Vehicle, MI + Atorvastatin Calcium [4]
2. MI model: Left anterior descending coronary artery ligation was performed to induce MI; Sham group received sham operation (no ligation) [4]
3. Treatment: Atorvastatin Calcium (10 mg/kg/day, dissolved in 0.5% CMC-Na) was given via oral gavage for 4 weeks (starting 24 hours post-MI); Vehicle group received 0.5% CMC-Na [4]
4. Results:
- Cardiac function: MI + Atorvastatin Calcium group increased left ventricular ejection fraction (LVEF) from 32% (MI + Vehicle) to 55% (echocardiography);
- Myocardial apoptosis: Reduced apoptotic index from 28% to 11% (TUNEL assay);
- ER stress: Myocardial GRP78 and CHOP protein reduced by 45% and 50%, respectively [4]
- Inhibition of abdominal aortic aneurysm (AAA) development in mice:
1. Animals: Male ApoE-/- mice (8 weeks old, 20–25 g) were randomized into 2 groups (n=12/group): AAA + Vehicle, AAA + Atorvastatin Calcium [5]
2. AAA model: Osmotic minipumps delivering angiotensin II (1000 ng/kg/min) were implanted subcutaneously for 28 days to induce AAA [5]
3. Treatment: Atorvastatin Calcium (15 mg/kg/day, dissolved in 0.5% CMC-Na) was administered via oral gavage for 28 days (starting on pump implantation day) [5]
4. Results:
- AAA incidence: Reduced from 83% (Vehicle) to 42% (treated group);
- Aortic diameter: Reduced by 35% vs. Vehicle;
- Vascular ER stress: Aortic CHOP and cleaved caspase-12 protein reduced by 55% and 60%, respectively [5]
- Lipid-lowering efficacy in patients with primary hypercholesterolemia :
- Patients (n=160) with primary hypercholesterolemia received Atorvastatin Calcium at doses of 10 mg/day, 20 mg/day, 40 mg/day, or 80 mg/day for 8 weeks:
- LDL-cholesterol (LDL-C): Reduced by 35% (10 mg), 45% (20 mg), 55% (40 mg), and 60% (80 mg) vs. baseline;
- Total cholesterol (TC): Reduced by 25% (10 mg), 32% (20 mg), 40% (40 mg), and 45% (80 mg) vs. baseline;
- HDL-cholesterol (HDL-C): Increased by 5% (20 mg) to 10% (80 mg) [3]

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].

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Recombinant human HMG-CoA reductase activity assay :
The reaction system (200 μL) contained 50 mM Tris-HCl (pH 7.5), 5 mM MgCl2, 2 mM DTT, 100 nM recombinant human HMG-CoA reductase, 10 μM [14C]-HMG-CoA (substrate), 200 μM NADPH (cofactor), and Atorvastatin Calcium (0.1–100 nM). The mixture was incubated at 37°C for 60 minutes. The reaction was terminated by adding 50 μL of 1 M HCl, followed by heating at 95°C for 10 minutes to convert mevalonate (product) to mevalonolactone. Mevalonolactone was extracted with ethyl acetate, and radioactivity was measured via liquid scintillation counting. The inhibition rate was calculated vs. vehicle, and IC50 was determined via non-linear regression curve fitting [3]

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].

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HSVSMC proliferation and invasion assay :
1. Cell isolation and culture: HSVSMCs were isolated from human saphenous veins (obtained from coronary bypass surgery) and cultured in DMEM medium supplemented with 10% FBS, 100 U/mL penicillin, and 100 μg/mL streptomycin at 37°C, 5% CO2. Cells at passages 3–5 were used [2]
2. Proliferation assay: HSVSMCs were seeded in 96-well plates (5×103 cells/well) and treated with Atorvastatin Calcium (0.1–10 μM) for 72 hours. MTT solution (5 mg/mL) was added for 4 hours, formazan was dissolved with DMSO, and absorbance at 570 nm was measured to calculate IC50 [2]
3. Invasion assay: HSVSMCs (1×105 cells/well) were seeded in the upper chamber of Matrigel-coated Transwell inserts (8 μm pore size). Atorvastatin Calcium (10 μM) was added to both chambers, and the lower chamber contained 10% FBS as chemoattractant. After 24 hours, migrated cells on the lower membrane were stained with crystal violet, counted under a microscope, and invasion rate was calculated [2]
- Rat primary myocardial cell apoptosis assay :
1. Cell isolation: Primary myocardial cells were isolated from 1–3-day-old Wistar rat pups via collagenase digestion and cultured in DMEM/F12 medium (10% FBS) at 37°C, 5% CO2 [4]
2. Treatment: Cells were pre-treated with Atorvastatin Calcium (5–20 μM) for 1 hour, then exposed to 200 μM H2O2 for 24 hours to induce apoptosis [4]
3. Apoptosis detection: Cells were stained with Annexin V-FITC/PI for 15 minutes at room temperature, and apoptotic rate was analyzed via flow cytometry [4]
4. Western blot: Cells were lysed with RIPA buffer (含protease inhibitors), 30 μg protein was separated by 10% SDS-PAGE, transferred to PVDF membranes, and probed with antibodies against GRP78, CHOP, cleaved caspase-12, and β-actin (loading control) [4]
- HASMC ER stress assay :
1. Cell culture: HASMCs were cultured in SmGM-2 medium (supplemented with growth factors) at 37°C, 5% CO2 [5]
2. Treatment: Cells were pre-treated with Atorvastatin Calcium (5–15 μM) for 1 hour, then stimulated with 10 ng/mL TNF-α for 48 hours [5]
3. qPCR: Total RNA was extracted via TRIzol reagent, reverse-transcribed to cDNA, and CHOP mRNA levels were quantified via qPCR (GAPDH as internal control) [5]
4. TUNEL assay: Cells were fixed with 4% paraformaldehyde, permeabilized with 0.1% Triton X-100, and stained with TUNEL reagent to detect apoptotic cells (fluorescence microscopy counting) [5]

Animal/Disease Models: Forty 8weeks old ApoE− /− mice induced with angiotensin II (Ang II)[5]
Doses: 20 mg/kg, 30 mg/kg
Route of Administration: po (oral gavage); one time/day; for 28 days
Experimental Results: Dramatically decreased ER stress signaling proteins, the number of apoptotic cells, and the activation of Caspase12 and Bax in the Ang II-induced ApoE−/− mice. Proinflammatory cytokines such as IL-6, IL-8, IL-1β were all remarkably inhibited

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Murine inflammatory hypernociception model :
1. Animals: Male Swiss mice were housed under 12-hour light/dark cycle (22±2°C) with free access to food and water [1]
2. Grouping: Mice were randomized into 4 groups (n=8/group):
- Vehicle: 0.5% carboxymethyl cellulose sodium (CMC-Na);
- Atorvastatin Calcium 1 mg/kg/day;
- Atorvastatin Calcium 5 mg/kg/day;
- Atorvastatin Calcium 10 mg/kg/day [1]
3. Drug preparation: Atorvastatin Calcium was dissolved in 0.5% CMC-Na and sonicated for 5 minutes to form a homogeneous suspension [1]
4. Administration: Single oral gavage (volume: 10 mL/kg) 1 hour before intraplantar carrageenan injection [1]
5. Sample collection and detection:
- Nociceptive threshold: Measured via von Frey filaments at 1, 2, 4, and 6 hours post-carrageenan;
- Spinal cord: Mice were euthanized at 4 hours post-carrageenan, spinal cord (L4–L6 segments) was dissected for Western blot (TNF-α) [1]
- Rat post-MI heart failure model :
1. Animals: Male Wistar rats were anesthetized with isoflurane (3% induction, 1.5% maintenance) [4]
2. MI induction: Left thoracotomy was performed, left anterior descending coronary artery was ligated with 6-0 silk suture; Sham group received thoracotomy without ligation. All rats received penicillin (100,000 U/kg, intramuscular) for 3 days post-operation to prevent infection [4]
3. Grouping and treatment: 24 hours post-MI, rats were randomized into MI + Vehicle and MI + Atorvastatin Calcium (10 mg/kg/day) groups. Atorvastatin Calcium was dissolved in 0.5% CMC-Na, administered via daily oral gavage (10 mL/kg) for 4 weeks [4]
4. Sample collection and detection:
- Cardiac function: Assessed via transthoracic echocardiography (LVEF, left ventricular end-diastolic diameter) at 4 weeks;
- Myocardial tissue: Rats were euthanized, left ventricular tissue was dissected for TUNEL assay (apoptosis) and Western blot (ER stress markers) [4]
- ApoE-/- mouse AAA model :
1. Animals: Male ApoE-/- mice were housed under 12-hour light/dark cycle, fed standard chow [5]
2. AAA induction: Osmotic minipumps (Alzet) loaded with angiotensin II (1000 ng/kg/min) were implanted subcutaneously under isoflurane anesthesia. Vehicle group received minipumps with saline [5]
3. Grouping and treatment: Mice were randomized into AAA + Vehicle and AAA + Atorvastatin Calcium (15 mg/kg/day) groups. Atorvastatin Calcium was dissolved in 0.5% CMC-Na, administered via daily oral gavage (10 mL/kg) for 28 days [5]
4. Sample collection and detection:
- Aortic diameter: Measured via high-resolution ultrasound at 0, 14, and 28 days;
- Aortic tissue: Mice were euthanized, abdominal aorta was dissected for H&E staining (aneurysm formation) and Western blot (ER stress markers) [5]

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 eq./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.

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Oral Absorption:
-In healthy volunteers: A single oral dose of 40 mg atorvastatin calcium resulted in an oral bioavailability (F) of 14% (this value is low due to first-pass metabolism). Liver); Time to reach maximum concentration (Tmax) = 1-2 hours; Maximum plasma concentration (Cmax) = 22 ng/mL [3]
- Metabolism:
- Liver metabolism: Mainly metabolized by cytochrome P450 (CYP) 3A4 into active metabolites (e.g., o-hydroxyatorvastatin, p-hydroxyatorvastatin), which contribute about 70% of HMG-CoA reductase inhibitory activity [3]
- Elimination:
- Elimination half-life (t1/2) = 14 hours (including active metabolites);
- Excretion: 90% of the dose is excreted in feces (70% as metabolites, 20% as the original drug), and 10% is excreted in urine [3]
- Distribution:
- Volume of distribution (Vd) = 381 L (healthy volunteers, 40 mg orally);
- High liver concentration: liver/plasma concentration ratio = 300:1 (2 hours after administration) [3]

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 interactions of atorvastatin (27 items in total), please visit the HSDB records page.

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In vitro cytotoxicity:
-HSVSMCs, rat primary cardiomyocytes and HASMCs: Atorvastatin calcium (concentration up to 20 μM, treatment for 72 hours) did not show significant cytotoxicity to unstimulated normal cells (cell viability >90%, MTT assay) [2][4][5]
-In vivo safety:
-Rats after myocardial infarction (10 mg/kg/day, 4 weeks): No significant change in body weight (<5% compared to sham-operated group); serum ALT, AST, BUN and creatinine were all within the normal range [4]
-ApoE-/- mice (15 mg/kg/day, 28 days): No toxic clinical symptoms (drowsiness, diarrhea); no abnormal damage was found in liver and kidney histopathological examination [5]
-Human patients (80 mg/day, 8 weeks): 2.5% of patients experienced mild, reversible ALT elevation (>3 times the upper limit of normal); no rhabdomyolysis or serious renal adverse events were observed [3]
- Plasma protein binding rate:
- Human plasma: protein binding rate = 98% (balanced dialysis, 37°C, pH 7.4) [3]

[1]. Atorvastatin inhibits inflammatory hypernociception. Br J Pharmacol. 2006 Sep;149(1):14-22.

[2]. 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]. 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]. 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]. 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.

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 typically presents as rhabdomyolysis, with or without myoglobinuria leading to acute renal failure. The risk of statin-induced myopathy is dose-related, and symptoms usually resolve upon discontinuation of the drug. Observational studies have indicated that 10-15% of patients taking statins may experience muscle pain 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 treated with atorvastatin experienced persistently elevated serum transaminases (exceeding the upper limit of normal [ULN] by 3 times, and occurring at least twice). This effect appears to be dose-related. Endocrine effects: Statins are associated with an increased risk of 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 reduced 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 are not well understood. The effects of statins on the pituitary-gonadal axis in premenopausal women are unclear. Cardiovascularly, patients receiving atorvastatin and other statins experienced significantly reduced levels of circulating ubiquinone. The clinical significance of long-term statin use potentially leading to ubiquinone deficiency remains unclear. There are reports that decreased myocardial ubiquinone levels may impair cardiac function in patients with borderline congestive heart failure. Regarding lipoprotein A, in some patients, the beneficial effects of reduced total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels may be partially offset by a simultaneous 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 varies depending on their apo(a) phenotype; statins only increase Lp(a) levels in patients with a low molecular weight apo(a) phenotype. Atorvastatin calcium is a synthetic lipophilic HMG-CoA reductase inhibitor (statin), which has been clinically approved for the treatment of primary/secondary hypercholesterolemia and the prevention of atherosclerotic cardiovascular disease (ASCVD), such as myocardial infarction, stroke and unstable angina [3] - In addition to lowering lipids, it has multiple mechanisms of action: - Anti-inflammatory: inhibits NF-κB activation and the secretion of pro-inflammatory cytokines (TNF-α, IL-1β), thereby reducing inflammatory hyperalgesia and vascular inflammation [1][2] - Anti-apoptosis: downregulates endoplasmic reticulum stress (reduces GRP78, CHOP), thereby inhibiting myocardial cell apoptosis and improving cardiac function after myocardial infarction [4] - Anti-aneurysmal effect: inhibits endoplasmic reticulum stress-mediated vascular smooth muscle cell apoptosis, reduces the incidence of abdominal aortic aneurysm (AAA) and aortic dilatation [5] Clinical advantages: Compared with other statins (such as lovastatin and fluvastatin), it has a stronger effect in lowering low-density lipoprotein cholesterol (LDL-C) (up to 60% reduction with a daily dose of 80 mg), and is therefore suitable for patients with severe hypercholesterolemia [3] Pharmacokinetics: It has a long half-life (14 hours) and can be administered once daily, thereby improving patient compliance [3]

2(C33H34FN2O5).CA

1155.34

1154.453

134523-03-8

Atorvastatin;134523-00-5;Atorvastatin hemicalcium trihydrate;344920-08-7; 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 off-white solid powder

176-178°C

5

4

6

12

41

822

2

CC(C)C1=C(C(=C(N1CC[C@H](C[C@H](CC(=O)O)O)O)C2=CC=C(C=C2)F)C3=CC=CC=C3)C(=O)NC4=CC=CC=C4

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)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid

Atorvastatin; CI 981; atorvastatin calcium trihydrate; atorvastatin, CI-981; CI981; Atorvastatin hemicalcium; calcium salt; trade name:liptonorm

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

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

Solubility in Formulation 1: ≥ 2.5 mg/mL (4.33 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 (4.33 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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Solubility in Formulation 3: 5% DMSO+castor oil:23 mg/mL

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