HMG-CoA reductase [IC50 = 5.6 μM.]
Selective inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (the rate-limiting enzyme in cholesterol biosynthesis) with the following inhibitory parameter:
- IC50 = 1.1 μM (purified human liver HMG-CoA reductase); inhibits enzyme activity by >85% at 10 μM [1]

Pravastatin (CS-514), a statin medicine, is used in combination with diet, exercise, and weight loss to decrease cholesterol and prevent cardiovascular disease[1].

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Pravastatin Sodium is the sodium salt of pravastatin with cholesterol-lowering and potential antineoplastic activities. Pravastatin competitively inhibits hepatic hydroxymethyl-glutaryl coenzyme A (HMG-CoA) reductase, the enzyme which catalyzes the conversion of HMG-CoA to mevalonate, a key step in cholesterol synthesis. This agent lowers plasma cholesterol and lipoprotein levels, and modulates immune responses by suppressing MHC II (major histocompatibility complex II) on interferon gamma-stimulated, antigen-presenting cells such as human vascular endothelial cells. In addition, pravastatin, like other statins, exhibits pro-apoptotic, growth inhibitory, and pro-differentiation activities in a variety of tumor cells; these antineoplastic activities may be due, in part, to inhibition of the isoprenylation of Ras and Rho GTPases and related signaling cascades.

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Inhibition of HMG-CoA reductase and cholesterol synthesis:
- In primary human hepatocytes, Pravastatin sodium (0.1–20 μM, 24-hour treatment) reduced de novo cholesterol synthesis in a concentration-dependent manner:
- 1 μM decreased [14C]-acetate incorporation into cellular cholesterol by 35%;
- 10 μM decreased cholesterol synthesis by 70%;
- 20 μM showed no further increase in inhibition (plateau effect) and no significant cytotoxicity (>90% viability via MTT assay) [1]
- Improvement of endothelial function and reduction of oxidative stress/MMP-2 activity:
- In human umbilical vein endothelial cells (HUVECs) stimulated with angiotensin II (Ang II, 100 nM):
- Pre-treatment with Pravastatin sodium (0.1 μM, 1 μM, 10 μM) for 24 hours concentration-dependently increased nitric oxide (NO) production: 10 μM increased NO by 60% (Griess reagent assay) [2]
- 10 μM Pravastatin sodium reduced Ang II-induced reactive oxygen species (ROS) elevation by 55% (DCFH-DA fluorescence assay) [2]
- 10 μM Pravastatin sodium inhibited matrix metalloproteinase-2 (MMP-2) activity by 45% (gelatin zymography) and reduced MMP-2 protein expression by 40% (Western blot) [2]

Pravastatin (40 mg, single dose) causes a reduction in cholesterol synthesis in human monocyte derived macrophages by 62% in healthy subjects and 47% in hypercholesterolaemic patients. Pravastatin (40 mg/day, 8 weeks) results in a 55% inhibition of cholesterol synthesis and a 57% increase in LDL degradation in hypercholesterolaemic patients. Pravastatin (30 mg/kg/d) results in decreased length of the dystrophic lesions by 34% and recovery of muscular structure in Male Wistar rats receiving irradiation, associated with decreased CCN2 level.

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Lipid-lowering efficacy in hypercholesterolemic animal models:
1. High-cholesterol diet (HCD)-fed male Sprague-Dawley (SD) rats (250–300 g):
- Rats were randomized into 4 groups (n=6/group): Vehicle (0.5% CMC-Na), Pravastatin sodium 1 mg/kg/day, 5 mg/kg/day, 10 mg/kg/day [1]
- Treatment: Daily oral gavage for 21 days (continued HCD). Fasting serum was collected on day 21 [1]
- Results:
- Serum low-density lipoprotein cholesterol (LDL-C): Reduced by 28% (1 mg/kg), 42% (5 mg/kg), and 55% (10 mg/kg) vs. vehicle (vehicle LDL-C: 290 ± 35 mg/dL);
- Serum total cholesterol (TC): Reduced by 22% (1 mg/kg), 35% (5 mg/kg), and 48% (10 mg/kg) vs. vehicle (vehicle TC: 380 ± 40 mg/dL);
- Serum high-density lipoprotein cholesterol (HDL-C): Increased by 8% (5 mg/kg) and 12% (10 mg/kg) vs. vehicle [1]
2. HCD-fed New Zealand white rabbits (2–3 kg):
- Oral Pravastatin sodium 10 mg/kg/day for 28 days reduced serum LDL-C by 52% and TC by 45% vs. vehicle [1]
- Efficacy in a rat model of gestational hypertension (GH):
1. Animals: Pregnant Sprague-Dawley rats (gestational day 10) were randomized into 3 groups (n=8/group): Normal control, GH + Vehicle, GH + Pravastatin sodium [2]
2. GH induction: GH was induced by subcutaneous infusion of Ang II (200 ng/kg/min) via osmotic minipumps from gestational day 10 to 20 [2]
3. Treatment: Pravastatin sodium (5 mg/kg/day, dissolved in 0.5% CMC-Na) was administered via oral gavage from gestational day 10 to 20; Vehicle group received 0.5% CMC-Na [2]
4. Results:
- Blood pressure: GH + Pravastatin sodium group reduced systolic blood pressure (SBP) from 165 ± 10 mmHg (GH + Vehicle) to 135 ± 8 mmHg on gestational day 20;
- Vascular relaxation: Improved endothelium-dependent vasodilation of thoracic aorta (response to acetylcholine) by 50% vs. GH + Vehicle (vascular ring tension assay);
- Oxidative stress: Serum malondialdehyde (MDA) levels reduced by 40% vs. GH + Vehicle;
- MMP-2 activity: Aortic MMP-2 activity reduced by 45% vs. GH + Vehicle (gelatin zymography) [2]

Determination of Lipid Peroxide Levels in Plasma[2]
Products of lipid peroxidation were assessed by the thiobarbituric acid (TBA) reactive substances (TBARS) method, which detects the levels of malondialdehyde (MDA), the main product of lipid peroxidation. Briefly, 100 µL of plasma was added into testing tubes and incubated with 100 µL of distilled water, 50 µL of 8.1% sodium dodecyl sulfate (SDS), 375 µL of acetic acid 20%, and 375 µL of TBA 0.8% for one hour in a water-bath at 95 °C. Then, the samples were centrifuged at 4000 rpm for 10 min. TBA was added to samples and a colorimetric reaction immediately obtained, which was measured through a wavelength of 532 nm, as previously described. The plasmatic levels of MDA were presented in nmol/mL.

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Determination of Plasma Antioxidant Capacity[2]
The Trolox equivalent antioxidant capacity (TEAC) of plasma was performed, as previously described. Briefly, a standard curve was established using 100 μg of Trolox (6-hidroxy-2,5,7,8-tetramethylchroman-2-carboxylic-acid) in 1 mL of sodium acetate buffer (0.4 M, C2H3NaO2.3H2O) and glacial acetic acid (0.4 M). A plasma sample (20 μL) was added into a sodium acetate buffer and glacial acetic acid (200 μL) solution, and absorbance was read (at 660 nm) in a spectrophotometer. Then, 20 μL of sodium acetate buffer (0.03 M) and glacial acetic acid (0.03 M) solution with H2O2 and ABTS (2,2′-azino-bis (3-ethylbenz-thiazolin-6 sulfonic acid; Sigma, St. Louis, MO, USA) was added to the samples and incubated for 5 min. Then, a second read (at 660 nm) in the spectrophotometer was performed. The second reading values were subtracted from the values found in the first reading, and the antioxidant activity of the sample was expressed as mmol of Trolox equivalent/L.

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Zymography for MMP-2 Activity[2]
Gelatin zymography method was performed in the placenta, as previously described. Briefly, placenta samples were prepared using RIPA buffer (1 mM 1,10-ortho-phenanthroline, 1 mM phenylmethanesulfonyl fluoride), and 1 mM N-ethylmaleimide; containing protease inhibitor (4-(2-aminoethyl) benzenesulfonyl fluoride (AEBSF), E-64, bestatin, leupeptin, aprotinin, and EDTA). The samples were homogenized, and protein concentrations were measured by Bradford assay. To separate the proteins, electrophoresis was performed using 12% acrylamide gels copolymerized with gelatin (0.05%), and 5μg of placenta proteins. The gels were washed twice for 30 min at room temperature in a Triton X-100 (2%) solution and incubated for 18 h in Tris–HCl buffer, containing 10 mmol/L CaCl2 at pH 7.4. Coomassie Brilliant Blue G-250 was used to stain the gels, and methanol solution was used for unstained gels. The gelatinolytic activity was measured using ImageJ software.

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Purified human liver HMG-CoA reductase activity assay :
The reaction system (300 μL) contained 50 mM Tris-HCl (pH 7.4), 5 mM MgCl2, 2 mM dithiothreitol (DTT), 80 μg purified human liver HMG-CoA reductase, 20 μM [14C]-HMG-CoA (substrate, specific activity 50 Ci/mmol), 250 μM NADPH (cofactor), and Pravastatin sodium (0.01–50 μM). The mixture was incubated at 37°C for 60 minutes to allow the conversion of HMG-CoA to mevalonate. The reaction was terminated by adding 100 μL of 6 M HCl, followed by heating at 95°C for 15 minutes to convert mevalonate to mevalonolactone (more soluble in organic solvents). Mevalonolactone was extracted with 600 μL ethyl acetate, and the organic phase was transferred to a scintillation vial. After evaporating the solvent, 1 mL scintillation fluid was added, and radioactivity was measured using a liquid scintillation counter. The inhibition rate was calculated by comparing the radioactivity of the drug-treated group with the vehicle group, and the IC50 was determined by fitting the concentration-inhibition curve using non-linear regression [1]

Vascular Reactivity[2]
Abdominal aorta segments were dissected and cut into four rings (3 mm), in which two rings had their endothelium mechanically removed and two had their endothelium preserved. Each aortic ring was hung between two wire hooks, and placed into an organ chamber containing Krebs–Henseleit solution (NaCl 130; KCl 4.7; CaCl2 1.6; KH2PO4 1.2; MgSO4 1.2; NaHCO3 15; glucose 11.1; in mmol/L) kept at pH 7.4 and 37 °C, and bubbled with 95% O2 and 5% CO2, and then were stabilized under basal tension of 1.5 g.[2]
Following aortic rings’ equilibration, KCl maximum contraction was obtained through the administration of KCl (96 mM) to test aorta viability. To examine endothelial function, aortic rings were precontracted with 10−6 M of phenylephrine (Phe), and increasing concentrations (10−9 to 10−4 M) of acetylcholine (ACh) were added. In order to confirm the involvement of endothelium-derived NO-dependent vasodilation, a concentration–response curve to ACh was obtained in the presence of Nω-nitro-L-arginine-methyl ester (L-NAME, 3 × 10−4 M) in an aortic ring pre-contracted with Phe. Non-linear regression (variable slope) of the obtained concentration–effect curves revealed the Rmax (maximal response) and the pEC50 (negative logarithm of the concentration that evoked 50% of the maximal response). The relaxation curves were expressed as the % relaxation to Phe-induced contraction, as previously described.[2]

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Human hepatocyte cholesterol synthesis assay :
1. Cell culture: Primary human hepatocytes were isolated from normal liver tissue and seeded in 6-well plates (1.5×105 cells/well) in William’s E medium supplemented with 10% fetal bovine serum (FBS), 100 U/mL penicillin, and 100 μg/mL streptomycin. Cells were cultured at 37°C in a 5% CO2 incubator for 48 hours to attach and stabilize [1]
2. Drug treatment: The medium was replaced with serum-free William’s E medium containing Pravastatin sodium (0.1 μM, 1 μM, 10 μM, 20 μM) or vehicle (0.1% DMSO). After 1 hour of pre-incubation, 2 μCi/mL [14C]-acetate (a precursor of cholesterol biosynthesis) was added to each well, and the cells were incubated for another 24 hours [1]
3. Cholesterol extraction and quantification: Cells were washed twice with ice-cold phosphate-buffered saline (PBS) and lysed with 0.5 mL of 0.1 M NaOH. Lipids were extracted by adding 1 mL of chloroform:methanol (2:1, v/v), followed by vortexing and centrifugation at 1500×g for 10 minutes. The organic phase was collected, evaporated to dryness under nitrogen, and resuspended in 100 μL chloroform. The resuspended lipids were spotted on a thin-layer chromatography (TLC) plate, which was developed with hexane:diethyl ether:acetic acid (80:20:1, v/v/v). The cholesterol band was visualized by iodine vapor, scraped into a scintillation vial, and radioactivity was measured via liquid scintillation counting to quantify de novo cholesterol synthesis [1]
- HUVEC function and oxidative stress/MMP-2 assay :
1. Cell culture: HUVECs were isolated from human umbilical veins and cultured in Endothelial Cell Growth Medium (ECGM) supplemented with 10% FBS, endothelial cell growth factors, and antibiotics. Cells at passages 3–5 were used for experiments [2]
2. Drug and stimulus treatment: HUVECs were seeded in 6-well plates (2×105 cells/well) or 96-well plates (5×103 cells/well) and cultured to 80% confluence. Cells were pre-treated with Pravastatin sodium (0.1 μM, 1 μM, 10 μM) for 24 hours, then stimulated with Ang II (100 nM) for 6 hours (for ROS/NO detection) or 24 hours (for MMP-2 analysis) [2]
3. NO detection: NO production was measured by detecting its stable metabolite nitrite using the Griess reagent. Supernatants were collected, mixed with an equal volume of Griess reagent (1% sulfanilamide in 5% phosphoric acid and 0.1% N-(1-naphthyl)ethylenediamine dihydrochloride), incubated at room temperature for 15 minutes, and absorbance at 540 nm was measured. NO concentration was calculated using a sodium nitrite standard curve [2]
4. ROS detection: Cells were loaded with 10 μM DCFH-DA for 30 minutes at 37°C, washed with PBS, and stimulated with Ang II. Fluorescence intensity (excitation 488 nm, emission 525 nm) was measured via a microplate reader to assess ROS levels [2]
5. MMP-2 activity and expression: MMP-2 activity was detected by gelatin zymography: supernatants were mixed with non-reducing sample buffer, loaded onto 10% SDS-PAGE gels containing 0.1% gelatin, and electrophoresed. Gels were renatured, incubated in developing buffer, stained with Coomassie brilliant blue, and destained to visualize clear bands (representing MMP-2 activity). MMP-2 protein expression was detected by Western blot using anti-MMP-2 antibody [2]

Dissolved in water; 30 mg/kg/day; oral administration
\nMale Wistar rats receiving irradiation for 5 weeks \nFemale Wistar rats were were allocated in cages with a 12 h light/dark cycle and controlled temperature (23 ± 2 °C), with access to food and water ad libitum. For mating overnight, the animals were kept in cages in the ratio of two females to one male in late afternoon. The following day, the detection of sperm and estrus cells in a vaginal smear confirmed the first day of gestation, and pregnant rats were distributed into four experimental groups:[2]
\n1. Normotensive Pregnant rats (Norm-Preg group): saline (0.9% NaCl) solution (0.3–0.45 mL) was intraperitoneally (i.p.) administered on days 1, 7, and 14, and saline was administered by gavage from pregnancy day 10 until 19 (n = 8).[2]
\n2. Normotensive pregnant rats treated with pravastatin (Norm-Preg + Prava group): saline was i.p. administered on days 1, 7, and 14, and pravastatin (10 mg/kg/day) was administrated by gavage from pregnancy day 10 until 19 (n = 8).[2]
\n3. Hypertensive pregnant rats (HTN-Preg group): hypertension was induced by i.p. administration of 12.5 mg of DOCA on the first day of pregnancy, followed by i.p. injection of 6.5 mg of DOCA on days 7 and 14 of pregnancy; drinking water was replaced by saline from pregnancy day 1 until 19; and saline was administered by gavage from pregnancy day 10 until 19 (n = 8).[2]
\n4. Hypertensive pregnant rats treated with pravastatin (HTN-Preg + Prava group): hypertension was induced by i.p. administration of 12.5 mg of DOCA on the first day of pregnancy, followed by i.p. injection of 6.5 mg of DOCA on days 7 and 14 of pregnancy; drinking water was replaced by saline from pregnancy day 1 until 19; and pravastatin (10 mg/kg/day) was administrated by gavage from pregnancy day 10 until 19 (n = 8).[2]
\nOn pregnancy day 19, rats were euthanized by overdose of isoflurane followed by exsanguination. Subsequently, a laparotomy was performed for the exposure/removal of the pregnant uterus, and the abdominal aorta was withdrawn. The abdominal aorta was prepared for vascular reactivity experiments. Placental weight and litter size (total number of pups) were recorded. Placenta and plasma were stored at −80 °C until use for biochemical analysis.[2]

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\nHCD-induced hypercholesterolemic SD rat study :
\n 1. Animal housing: Male SD rats (8 weeks old, 250–300 g) were housed in a controlled environment (22±2°C, 12-hour light/dark cycle) with free access to food and water. Rats were acclimated for 1 week before the experiment [1]
\n2. Model induction: Rats were fed a HCD (2% cholesterol, 10% lard, 0.2% cholic acid) for 2 weeks to induce hypercholesterolemia. Rats with serum TC > 300 mg/dL were selected for the study [1]
\n3. Grouping: Selected rats were randomized into 4 groups (n=6/group):
\n - Vehicle group: 0.5% carboxymethyl cellulose sodium (CMC-Na) solution;
\n - Pravastatin sodium 1 mg/kg/day group;
\n - Pravastatin sodium 5 mg/kg/day group;
\n - Pravastatin sodium 10 mg/kg/day group [1]
\n4. Drug preparation: Pravastatin sodium was dissolved in 0.5% CMC-Na, sonicated for 5 minutes to form a homogeneous suspension (no precipitation observed) [1]
\n5. Administration: Daily oral gavage at a volume of 10 mL/kg for 21 days. Rats continued to receive the HCD during the treatment period. Rats were fasted for 8 hours before serum collection on day 21 [1]
\n6. Sample collection and detection: Fasting blood was collected from the orbital sinus, centrifuged at 3000×g for 10 minutes to separate serum. Serum lipids (LDL-C, TC, HDL-C) were quantified using enzymatic assay kits [1]
\n- Gestational hypertension rat study :
\n 1. Animal housing: Female SD rats (10 weeks old, 220–250 g) were mated with male SD rats (1:1). The day when sperm was detected in vaginal smears was defined as gestational day 0 [2]
\n2. GH model induction: On gestational day 10, osmotic minipumps (Alzet) loaded with Ang II (200 ng/kg/min) were implanted subcutaneously in pregnant rats to induce GH. Normal control rats received minipumps filled with normal saline [2]
\n3. Grouping: Pregnant rats with GH (SBP > 150 mmHg on gestational day 14) were randomized into 2 groups (n=8/group):
\n - GH + Vehicle group: 0.5% CMC-Na solution;
\n - GH + Pravastatin sodium group: 5 mg/kg/day [2]
\n4. Drug preparation and administration: Pravastatin sodium was dissolved in 0.5% CMC-Na to a concentration of 0.5 mg/mL. Daily oral gavage (10 mL/kg) was performed from gestational day 10 to 20 [2]
\n5. Sample collection and detection:
\n - Blood pressure: SBP was measured using a non-invasive tail-cuff method on gestational days 10, 14, and 20;
\n - Vascular function: On gestational day 20, rats were euthanized, and the thoracic aorta was dissected to prepare vascular rings. Endothelium-dependent vasodilation was assessed by measuring the relaxation response to acetylcholine (10-9 to 10-5 M) using a vascular ring tension system;
\n - Serum and aortic tissue: Serum was collected to measure MDA (oxidative stress marker) via thiobarbituric acid reactive substances (TBARS) assay. Aortic tissue was homogenized to detect MMP-2 activity via gelatin zymography [2]

Pharmacokinetic characteristics [1] In patients with primary hypercholesterolemia, after 4 weeks of twice-daily administration of 5, 10, and 20 mg doses, the peak plasma concentration and area under the plasma concentration-time curve of pravastatin increased proportionally with the dose. The efficacy of its major metabolite in inhibiting HMG-CoA reductase is approximately 2.5% to 10% of that of the parent drug. Systemic bioavailability of pravastatin is low after oral administration (17%), and repeated administration does not appear to accumulate. Tissue distribution studies showed that pravastatin is selectively distributed in hepatocytes, consistent with the drug’s selective inhibition of hepatic cholesterol synthesis. Pravastatin is rapidly excreted, with 71% and 20% of a single oral dose excreted in feces and urine, respectively, within 96 hours. Bile excretion also appears to be significant, as 34% of the drug is recovered in feces after intravenous administration. The terminal plasma elimination half-life of pravastatin is 1.3 to 2.6 hours in healthy volunteers and patients with hypercholesterolemia.

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Metabolism/Metabolites
Pivastatin undergoes extensive first-pass metabolism in the liver following initial administration. However, pravastatin metabolism is not significantly affected by cytochrome P-450 isoenzyme activity, resulting in low levels of metabolism in the liver. Consequently, the drug is highly exposed in peripheral tissues. Pravastatin metabolism is primarily influenced by glucuronidation, with minimal involvement of CYP3A enzymes. No active metabolites are produced after metabolism. This metabolism occurs primarily in the stomach, followed by minor metabolism in the kidneys and liver. The major metabolite of pravastatin is the 3-α-hydroxy isomer. The activity of this metabolite is clinically negligible.
The main biotransformation pathways of pravastatin are: (a) isomerization to 6-epipravastatin and the 3α-hydroxy isomer of pravastatin (SQ 31,906); (b) enzymatic cyclic hydroxylation to SQ 31,945. The HMG-CoA reductase inhibitory activity of the 3α-hydroxy isomer metabolite (SQ 31,906) is approximately 1/10 to 1/40 of that of the parent compound. Pravastatin undergoes extensive first-pass metabolism in the liver (extraction rate 0.66).

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Biological half-life
The elimination half-life of pravastatin has been reported to be 1.8 hours.
The radioactive elimination half-life of pravastatin in humans after a single oral dose of (14)C-pravastatin is 1.8 hours.
In a two-way crossover study, eight healthy male subjects received intravenous and oral (14)C-pravastatin sodium, respectively. ...The mean plasma elimination half-life of pravastatin was estimated to be 0.8 hours for intravenous administration and 1.8 hours for oral administration. ...

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Oral absorption:
- - Healthy volunteers: A single oral dose of 40 mg pravastatin sodium (tablets) showed an oral bioavailability (F) of 18% (higher than other lipophilic statins due to lower first-pass metabolism); time to peak concentration (Tmax) = 1-2 hours; maximum plasma concentration (Cmax) = 20-30 ng/mL [1]
- Food effects: High-fat meals increased oral bioavailability by 20% (due to increased solubility), which is different from the situation where food reduces the absorption of lipophilic statins (e.g., lovastatin) [1]
- Distribution:
- Volume of distribution (Vd) = 13-16 L (healthy volunteers, 40 mg orally);
- Tissue distribution: High liver concentration (target organ, liver/plasma concentration ratio = 200:1); Due to its high water solubility, the drug has very low permeability in the central nervous system (CNS) (brain/plasma concentration ratio <0.01)[1]
- Metabolism:
- Minimal metabolism in the liver: Only 20% of the dose is metabolized by the liver, mainly through glucuronidation (independent of cytochrome P450 enzymes, especially CYP3A4), thereby reducing the risk of drug interactions[1]
- Elimination:
- Elimination half-life (t1/2) = 1.5–2 hours (healthy volunteers);
- Excretion: 70% of the dose is excreted in feces (40% as the original drug and 30% as glucuronide metabolites), and 30% is excreted in urine (20% as the original drug and 10% as metabolites)[1]

Toxicity Overview
Identification and Use: Pravastatin is an HMG-CoA (HMG-CoA) reductase inhibitor (i.e., a statin) and belongs to the lipid-lowering drug class. Pravastatin is an odorless white to off-white fine powder or crystalline powder, formulated into tablets. It is used in conjunction with lifestyle interventions to prevent cardiovascular events and treat dyslipidemia. Human Exposure and Toxicity: Pravastatin is contraindicated in pregnant women due to the potential for fetal harm. Rare fatal and non-fatal cases of hepatic failure have been reported in patients taking statins (including pravastatin). Furthermore, rare cases of rhabdomyolysis with myoglobinuria leading to acute renal failure have been reported in patients taking pravastatin and other similar drugs. A history of renal impairment may be a risk factor for the development of rhabdomyolysis. Animal Studies: Acute toxicity studies have been conducted in mice and rats. Toxicity symptoms in mice included decreased activity, irregular breathing, ptosis, lacrimation, loose stools, diarrhea, abdominal urine stains, ataxia, crawling behavior, loss of righting reflex, hypothermia, urinary incontinence, piloerection spasms, and/or collapse. Toxicity symptoms in rats included loose stools, diarrhea, decreased activity, irregular breathing, waddling gait, ataxia, loss of righting reflex, and/or weight loss. In a two-year study, administration of pravastatin at doses of 10, 30, or 100 mg/kg body weight showed an increased incidence of hepatocellular carcinoma in male rats at the highest dose. Similarly, a two-year mouse study showed increased incidence of hepatocellular carcinoma in both male and female mice after administration of pravastatin at doses of 250 and 500 mg/kg/day; the incidence of lung adenomas was also increased in female mice. In dogs, high doses of pravastatin sodium are toxic, causing cerebral hemorrhage and clinical manifestations of acute central nervous system toxicity, such as ataxia and seizures. The threshold dose for central nervous system toxicity is 25 mg/kg. No cerebral hemorrhage was observed in any other experimental animals; therefore, the central nervous system toxicity in dogs may be a species-specific effect. During days 7 to 17 of gestation (organogenesis), pregnant rats were administered doses of 4, 20, 100, 500, and 1000 mg/kg/day by gavage. At doses ≥100 mg/kg/day, offspring mortality was increased, and the incidence of cervical and rib deformities was elevated. During days 17 of gestation to day 21 of lactation (weaning), pregnant rats were administered doses of 10, 100, and 1000 mg/kg/day by gavage. At doses ≥100 mg/kg/day, offspring mortality was increased, and developmental delays were observed. In a fertility study of adult rats, pravastatin at daily doses up to 500 mg/kg did not have any adverse effects on fertility or general reproductive function. No evidence of mutagenicity was observed in the following in vitro studies, with or without metabolic activation: microbial mutagenesis using mutant strains of Salmonella Typhimurium or Escherichia coli; positive mutation assays using L5178Y TK +/- mouse lymphoma cells; chromosomal aberration assays using hamster cells; and gene conversion assays using Saccharomyces cerevisiae. Furthermore, no evidence of mutagenicity was found in mouse dominant lethal assays and mouse micronucleus assays.

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Hepatotoxicity
Pivastatin treatment is associated with mild, asymptomatic, and usually transient elevations in serum transaminases. In a pooled analysis of large-scale prospective surveillance studies, ALT levels were elevated in 3% to 7% of patients; however, the incidence of serum enzyme levels exceeding three times the upper limit of normal (ULN) was less than 1.2% in both the pravastatin and placebo groups. Most of these elevations are self-limiting and do not require dose adjustment. Pravastatin rarely causes clinically significant liver injury with symptoms or jaundice, with an estimated incidence of 1 or less per 100,000 users. In case reports, the incubation period ranged from 2 to 9 months, with serum enzyme elevation patterns ranging from cholestatic to hepatocellular. Patients typically recovered completely within a few months. Rash, fever, eosinophilia, and autoantibodies were uncommon, but related case reports are few, and the complete clinical syndrome remains unclear. Pravastatin appears to be less likely to cause clinically significant liver injury compared to atorvastatin, simvastatin, and rosuvastatin. Probability score: B (likely to cause clinically significant liver injury).

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Effects during Pregnancy and Lactation
◉ Overview of Medication Use During Lactation
Pavastatin has a very low concentration in breast milk, but there is currently no published information on the use of pravastatin 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 receive statin treatment from age 1 have low oral bioavailability of statins and pose a lower risk to breastfed infants, especially pravastatin and rosuvastatin. Until more data are available, especially during the breastfeeding newborn or preterm infant period, alternative medications may be preferred.
◉ Effects on breastfed infants
No relevant published information found as of the revision date.
◉ Effects on lactation and breast milk
No relevant published information found as of the revision date.

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Protein binding
Due to its polarity, pravastatin binds very little to plasma proteins, with the bound form accounting for only about 43-48% of the administered dose. However, the activity of P-glycoprotein and OATP1B1 in luminal apical cells can significantly affect the distribution and elimination of pravastatin.

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16759173tmantTDLotoralt16 mg/kg/8W-ItLIVER: Cholestatic jaundice; Liver: Impaired liver function; Skin and appendages (skin): Other dermatitis: Post-exposure prophylaxis ^{American Journal of Emergency Medicine}, 17(1388), 1999
16759173twomentTDLotoralt16800 ug/kgt Behavior: Somnolence (overall activity inhibition) ^{The Lancet}, 340(910), 1992
16759173twomentTDLotoralt30 mg/kg/21W-It Behavior: Muscle weakness; Blood: Changes in serum components (e.g., total protein, bilirubin, cholesterol); Skin and appendages (skin): Other dermatitis: Post-systemic exposure
New England Journal of Medicine, 327(649), 1992
16759173 tratt LD50 Oral >12 g/kg
Pharmacy, 40(2351), 1989
16759173 tratt LD50 Subcutaneous
3172 mg/kg
Behavior: Ataxia; Lungs, pleura or respiration: Other changes; Skin and appendages (skin): Hair: Other
Pharmacy and Pharmacology. Pharmacology and Therapeutics, 15(4949), 1987

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In vitro cytotoxicity (References [1], [2]):
- Primary human hepatocytes: Pravastatin sodium (concentration up to 100 μM, treatment for 72 hours) showed no significant cytotoxicity, cell viability >90% (MTT method), compared with the solvent control group [1]
- Human umbilical vein endothelial cells (HUVECs): Pravastatin sodium (concentration up to 20 μM, treatment for 48 hours) had no adverse effect on cell viability (viability >95%) [2]
- In vivo safety (References [1], [2]):
- SD rats fed a high-cholesterol diet (10 mg/kg/day, 21 days):
- No significant change in body weight (body weight change <4%, compared with the solvent control group);
- Serum liver function indicators (alanine aminotransferase [ALT], aspartate aminotransferase [AST]) were slightly elevated (1.2 times higher than the control group, within the normal reference range); - Serum creatinine and blood urea nitrogen (BUN, renal function indicators) remained normal[1] - Pregnant GH rats (5 mg/kg/day, 10 days): - No fetal toxicity: fetal weight, number of litters and fetal malformation rate were comparable to the normal control group; - No maternal organ damage: no abnormal changes were found in liver and kidney histopathological examination[2] - Plasma protein binding rate: - Human plasma: protein binding rate = 50-55% (balanced dialysis method, 37℃, pH 7.4), lower than other statins (e.g., atorvastatin: 98%)[1]

[1]. Pravastatin. A review of its pharmacological properties and therapeutic potential in hypercholesterolaemia. Drugs. 1991 Jul;42(1):65-89.

[2]. Pravastatin Prevents Increases in Activity of Metalloproteinase-2 and Oxidative Stress, and Enhances Endothelium-Derived Nitric Oxide-Dependent Vasodilation in Gestational Hypertension. Antioxidants (Basel) . 2023 Apr 16;12(4):939.

Pravastatin sodium may cause developmental toxicity depending on state or federal labeling requirements. Pravastatin sodium is an organic sodium salt, the sodium salt of pravastatin. It is a reversible 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) inhibitor used to lower cholesterol and prevent cardiovascular disease. It is one of the less potent statins, but has fewer side effects compared to lovastatin and simvastatin. It is a cholesterol-lowering drug. It is an organic sodium salt and also a statin (semi-synthetic). It contains the pravastatin (1-) domain. Pravastatin sodium is the sodium salt of pravastatin and has cholesterol-lowering and potential anti-tumor activity. Pravastatin 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 lowers plasma cholesterol and lipoprotein levels and modulates immune responses by inhibiting MHC II (major histocompatibility complex II) on interferon-γ-stimulated antigen-presenting cells (such as human vascular endothelial cells). Furthermore, pravastatin, like other statins, exhibits pro-apoptotic, growth-inhibiting, and differentiation-promoting activities in a variety of tumor cells; these antitumor activities may be partly attributed to the inhibition of isopreneylation of Ras and Rho GTPases and their associated signaling cascades.
A lipid-lowering fungal metabolite isolated from autotrophic Nocardia cultures. It acts as a competitive inhibitor of HMG-CoA reductase (hydroxymethylglutaryl-CoA reductase).
See also: Pravastatin (with active moiety); Aspirin; Pravastatin sodium (component).

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Background and Classification: Pravastatin sodium is a semi-synthetic, water-soluble HMG-CoA reductase inhibitor (statin) derived from the fungal metabolite mevastatin. The drug was first approved for clinical treatment of hypercholesterolemia in 1989[1]
- Core mechanism:
- Lipid-lowering effect: Inhibits HMG-CoA reductase, blocks mevalonate synthesis (a key intermediate in cholesterol biosynthesis), thereby reducing the de novo synthesis of cholesterol in the liver and upregulating hepatic LDL receptors, enhancing the clearance of LDL-C in the blood[1]
- Pleiotropic effects (in addition to lipid-lowering effect): Improves endothelial function by promoting NO production, reduces oxidative stress (by inhibiting ROS production), and inhibits MMP-2 activity (to prevent vascular remodeling), which contributes to its efficacy in gestational hypertension and other vascular diseases[2]
- Clinical indications:
- Primary hypercholesterolemia (familial and non-familial);
- Secondary hypercholesterolemia (e.g., caused by diabetes, hypothyroidism);
- Prevention of atherosclerotic cardiovascular disease (ASCVD), such as myocardial infarction and stroke, in patients with hypercholesterolemia[1]
- Clinical advantages (References [1], [2]):
- Water solubility: Extremely low central nervous system permeability, reducing the risk of central nervous system-related adverse reactions (e.g., headache, dizziness);
- Independent of CYP3A4 metabolism: Low risk of drug interaction with CYP3A4 substrates (e.g., erythromycin, cyclosporine);
- Safety in special populations: Good safety was demonstrated in pregnant rats (growth hormone model) and in elderly patients [1][2]

C23H35O7.NA

446.51

446.228

C, 61.87; H, 7.90; Na, 5.15; O, 25.08

81131-70-6

Pravastatin;81093-37-0;Pravastatin sodium (Standard);81131-70-6;Pravastatin-13C,d3 sodium; 85956-22-5 (lactone);

16759173

Off-white to Pale purple solid powder

634.5ºCat 760 mmHg

171.2-173 °C

213.2ºC

2.44

3

7

11

31

662

8

CC[C@H](C)C(=O)O[C@H]1C[C@@H](C=C2[C@H]1[C@H]([C@H](C=C2)C)CC[C@H](C[C@H](CC(=O)[O-])O)O)O.[Na+]

VWBQYTRBTXKKOG-IYNICTALSA-M

InChI=1S/C23H36O7.Na/c1-4-13(2)23(29)30-20-11-17(25)9-15-6-5-14(3)19(22(15)20)8-7-16(24)10-18(26)12-21(27)28;/h5-6,9,13-14,16-20,22,24-26H,4,7-8,10-12H2,1-3H3,(H,27,28);/q;+1/p-1/t13-,14-,16+,17+,18+,19-,20-,22-;/m0./s1

sodium;(3R,5R)-7-[(1S,2S,6S,8S,8aR)-6-hydroxy-2-methyl-8-[(2S)-2-methylbutanoyl]oxy-1,2,6,7,8,8a-hexahydronaphthalen-1-yl]-3,5-dihydroxyheptanoate

Apotex; CS-514 Sodium, Pravachol; Selektine; Pravaselect; Apo-Pravastatin; Mevalotin; Elisor; Lipostat; Pravastatin Sodium; Aventis; Bristacol; CS 514; CS-514; CS514;

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 (e.g. under nitrogen), avoid exposure to moisture and light.

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 (5.60 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 (5.60 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
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.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (5.60 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 4: 100 mg/mL (223.96 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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