HMG-CoA reductase [IC50 = 5.6 μM.]

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.

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.

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.

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]

Female 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]
1. 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]
2. 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]
3. 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]
4. 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]
On 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]

Dissolved in water; 30 mg/kg/day; oral administration

Male Wistar rats receiving irradiation for 5 weeks

Pharmacokinetic Properties[1]
After 4 weeks of twice daily 5, 10 and 20mg doses peak plasma pravastatin concentrations and area under the plasma concentration-time curve values increased dose proportionally in patients with primary hypercholesterolaemia. The major metabolite is about 2.5 to 10% as potent as its parent drug with regard to inhibiting HMG-CoA reductase. Pravastatin has a low (17%) systemic availability after an oral dose and does not appear to accumulate with repeated administration. Tissue distribution studies have demonstrated that pravastatin is selectively distributed to hepatic cells, which is consistent with the drug’s selective inhibition of cholesterol synthesis in the liver. Pravastatin is excreted rapidly, with 71 and 20% of a single oral dose recovered in faeces and urine, respectively, within 96 hours. Biliary excretion appears to be marked since after intravenous administration 34% of the drug is recoverable in faeces. The terminal plasma elimination half-life of pravastatin in healthy volunteers and hypercholesterolaemic patients has ranged from 1.3 to 2.6 hours.

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Metabolism / Metabolites
After initial administration, pravastatin undergoes extensive first-pass extraction in the liver. However, pravastatin's metabolism is not related to the activity of the cytochrome P-450 isoenzymes and its processing is performed in a minor extent in the liver. Therefore, this drug is highly exposed to peripheral tissues. The metabolism of pravastatin is ruled mainly by the presence of glucuronidation reactions with very minimal intervention of CYP3A enzymes. After metabolism, pravastatin does not produce active metabolites. This metabolism is mainly done in the stomach followed by a minor portion of renal and hepatic processing. The major metabolite formed as part of pravastatin metabolism is the 3-alpha-hydroxy isomer. The activity of this metabolite is very clinically negligible.

The major biotransformation pathways for pravastatin are: (a) isomerization to 6-epi pravastatin and the 3a-hydroxyisomer of pravastatin (SQ 31,906) and (b) enzymatic ring hydroxylation to SQ 31,945. The 3a-hydroxyisomeric metabolite (SQ 31,906) has 1/10 to 1/40 the HMG-CoA reductase inhibitory activity of the parent compound. Pravastatin undergoes extensive first-pass extraction in the liver (extraction ratio 0.66).

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Biological Half-Life
The reported elimination half-life of pravastatin is reported to be of 1.8 hours.

Following single dose oral administration of (14)C-pravastatin, the radioactive elimination half life for pravastatin is 1.8 hours in humans.

In a two-way crossover study, eight healthy male subjects each received an intravenous and an oral dose of (14)C-pravastatin sodium. ... The estimated average plasma elimination half-life of pravastatin was 0.8 and 1.8 hr for the intravenous and oral routes, respectively. ...

Toxicity Summary
IDENTIFICATION AND USE: Pravastatin, a hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitor (i.e., statin), is an antilipemic agent. Pravastatin occurs as an odorless, white to off-white, fine or crystalline powder formulated into a tablet. It is used as an adjunct to lifestyle modifications for prevention of cardiovascular events and for the management of dyslipidemias. HUMAN EXPOSURE AND TOXICITY: Pravastatin is contraindicated for use in pregnant woman because of the potential for fetal harm. There have also been rare reports of fatal and non-fatal hepatic failure in patients taking statins, including pravastatin. Also, rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with pravastatin and other drugs in this class. A history of renal impairment may be a risk factor for the development of rhabdomyolysis. ANIMAL STUDIES: Acute studies were performed in both mice and rats. Signs of toxicity in mice were decreased activity, irregular respiration, ptosis, lacrimation, soft stool, diarrhea, urine-stained abdomen, ataxia, creeping behavior, loss of righting reflex, hypothermia, urinary incontinence, pilo-erection convulsion and/or prostration. Signs of toxicity in rats were soft stool, diarrhea, decreased activity, irregular respiration, waddling gait, and ataxia, loss of righting reflex and/or weight loss. In a 2-year study in rats fed pravastatin at doses of 10, 30, or 100 mg/kg bw, there was an increased incidence of hepatocellular carcinomas in males at the highest dose. Likewise, in a 2-year study in mice fed pravastatin at doses of 250 and 500 mg/kg/day, there was an increased incidence of hepatocellular carcinomas in males and females; lung adenomas in females were increased. In dogs, pravastatin sodium was toxic at high doses and caused cerebral hemorrhage with clinical evidence of acute CNS toxicity such as ataxia, convulsions. The threshold dose for CNS toxicity is 25 mg/kg. Cerebral hemorrhages have not been observed in any other laboratory species and the CNS toxicity in dogs may represent a species-specific effect. In pregnant rats given oral gavage doses of 4, 20, 100, 500, and 1000 mg/kg/day from gestation days 7 through 17 (organogenesis) increased mortality of offspring and increased cervical rib skeletal anomalies were observed at >/= 100 mg/kg/day. In pregnant rats given oral gavage doses of 10, 100, and 1000 mg/kg/day from gestation day 17 through lactation day 21 (weaning), increased mortality of offspring and developmental delays were observed at >/= 100 mg/kg/day. In a fertility study in adult rats with daily doses up to 500 mg/kg, pravastatin did not produce any adverse effects on fertility or general reproductive performance. No evidence of mutagenicity was observed in vitro, with or without metabolic activation, in the following studies: microbial mutagen tests, using mutant strains of Salmonella typhimurium or Escherichia coli; a forward mutation assay in L5178Y TK +/- mouse lymphoma cells; a chromosomal aberration test in hamster cells; and a gene conversion assay using Saccharomyces cerevisiae. In addition, there was no evidence of mutagenicity in either a dominant lethal test in mice or a micronucleus test in mice.

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Hepatotoxicity
Pravastatin therapy is associated with mild, asymptomatic and usually transient serum aminotransferase elevations. In summary analyses of large scale studies with prospective monitoring, ALT elevations above normal occurred in 3% to 7% of patients; but levels above 3 times the upper limit of normal (ULN) occurred in less than 1.2% of both pravastatin- as well as in placebo-treated subjects. Most of these elevations were self-limited and did not require dose modification. Pravastatin has been only rarely associated with clinically apparent hepatic injury with symptoms or jaundice at a rate estimated to be 1 per 100,000 users or less. In the case reports, latency varied from 2 to 9 months and the pattern of serum enzyme elevations from cholestatic to hepatocellular. Recovery was complete within a few months. Rash, fever and eosinophilia were uncommon as were autoantibodies, but few cases have been reported and the full clinical syndrome not well defined. Pravastatin appears to be less likely to cause clinically apparent liver injury than atorvastatin, simvastatin and rosuvastatin.
Likelihood score: B (likely cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Levels of pravastatin in milk are low, but no relevant published information exists with its use during breastfeeding. The consensus opinion is that women taking a statin should not breastfeed because of a concern with disruption of infant lipid metabolism. However, others have argued that children homozygous for familial hypercholesterolemia are treated with statins beginning at 1 year of age, that statins have low oral bioavailability, and risks to the breastfed infant are low, especially with pravastatin and rosuvastatin. Until more data become available, an alternate drug may be preferred, especially while nursing a newborn or preterm infant.

◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.

◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Due its polarity, pravastatin binding to plasma proteins is very limited and the bound form represents only about 43-48% of the administered dose. However, the activity of p-glycoprotein in luminal apical cells and OATP1B1 produce significant changes to pravastatin distribution and elimination.

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16759173 man TDLo oral 16 mg/kg/8W-I LIVER: JAUNDICE, CHOLESTATIC; LIVER: LIVER FUNCTION TESTS IMPAIRED; SKIN AND APPENDAGES (SKIN): DERMATITIS, OTHER: AFTER SYSTEMIC EXPOSURE American Journal of Emergency Medicine., 17(1388), 1999
16759173 women TDLo oral 16800 ug/kg BEHAVIORAL: SOMNOLENCE (GENERAL DEPRESSED ACTIVITY) Lancet., 340(910), 1992
16759173 women TDLo oral 30 mg/kg/21W-I BEHAVIORAL: MUSCLE WEAKNESS; BLOOD: CHANGES IN SERUM COMPOSITION (E.G., TP, BILIRUBIN, CHOLESTEROL); SKIN AND APPENDAGES (SKIN): DERMATITIS, OTHER: AFTER SYSTEMIC EXPOSURE New England Journal of Medicine., 327(649), 1992
16759173 rat LD50 oral >12 gm/kg Yakkyoku. Pharmacy., 40(2351), 1989
16759173 rat LD50 subcutaneous 3172 mg/kg BEHAVIORAL: ATAXIA; LUNGS, THORAX, OR RESPIRATION: OTHER CHANGES; SKIN AND APPENDAGES (SKIN): HAIR: OTHER Yakuri to Chiryo. Pharmacology and Therapeutics., 15(4949), 1987

[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 can cause developmental toxicity according to state or federal government labeling requirements.
Pravastatin sodium is an organic sodium salt that is the sodium salt of pravastatin. A reversible inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA), it is used for lowering cholesterol and preventing cardiovascular disease. It is one of the lower potency statins, but has the advantage of fewer side effects compared with lovastatin and simvastatin. It has a role as an anticholesteremic drug. It is an organic sodium salt and a statin (semi-synthetic). It contains a pravastatin(1-).
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.
An antilipemic fungal metabolite isolated from cultures of Nocardia autotrophica. It acts as a competitive inhibitor of HMG CoA reductase (HYDROXYMETHYLGLUTARYL COA REDUCTASES).
See also: Pravastatin (has active moiety); Aspirin; pravastatin sodium (component of).

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.)