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]

普伐他汀 (CS-514) 是一种他汀类药物，与饮食、运动和减肥相结合，可降低胆固醇并预防心血管疾病[1]。

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普伐他汀钠是普伐他汀的钠盐，具有降低胆固醇和潜在的抗肿瘤活性。普伐他汀竞争性抑制肝羟甲基戊二酰辅酶A （HMG-CoA）还原酶，该酶催化HMG-CoA转化为甲羟戊二酸，这是胆固醇合成的关键步骤。该药物降低血浆胆固醇和脂蛋白水平，并通过抑制干扰素γ刺激的抗原呈递细胞（如人血管内皮细胞）上的MHC II（主要组织相容性复合体II）来调节免疫反应。此外，普伐他汀和其他他汀类药物一样，在多种肿瘤细胞中表现出促凋亡、生长抑制和促分化活性；这些抗肿瘤活性可能部分是由于抑制Ras和Rho gtpase的异戊二烯化以及相关的信号级联反应。

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抑制HMG-CoA还原酶与胆固醇合成：
- 在原代人肝细胞中，普伐他汀钠（Pravastatin sodium） （0.1~20 μM，处理24小时）浓度依赖性减少新生胆固醇合成：
- 1 μM使[14C]-乙酸掺入细胞胆固醇的量减少35%；
- 10 μM使胆固醇合成减少70%；
- 20 μM时抑制效果达平台期，且无显著细胞毒性（MTT法检测活力>90%）[1]
- 改善内皮功能、降低氧化应激与MMP-2活性：
- 在血管紧张素II（Ang II，100 nM）刺激的人脐静脉内皮细胞（HUVECs）中：
- 普伐他汀钠（Pravastatin sodium） （0.1 μM、1 μM、10 μM）预处理24小时，浓度依赖性增加一氧化氮（NO）生成：10 μM使NO增加60%（Griess试剂法）[2]
- 10 μM 普伐他汀钠 使Ang II诱导的活性氧（ROS）升高降低55%（DCFH-DA荧光法）[2]
- 10 μM 普伐他汀钠 抑制基质金属蛋白酶-2（MMP-2）活性45%（明胶酶谱法），降低MMP-2蛋白表达40%（Western blot）[2]

普伐他汀（40 毫克，单剂量）可使健康受试者中人单核细胞来源的巨噬细胞的胆固醇合成减少 62%，使高胆固醇血症患者减少 47%。普伐他汀（40 毫克/天，8 周）可抑制高胆固醇血症患者的胆固醇合成 55%，并使 LDL 降解增加 57%。普伐他汀 (30 mg/kg/d) 可使接受照射的雄性 Wistar 大鼠营养不良病变长度缩短 34%，肌肉结构恢复，与 CCN2 水平降低相关。

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高胆固醇血症动物模型的降脂疗效：
1. 高脂饮食（HCD）喂养的雄性SD大鼠（250~300 g）：
- 大鼠随机分为4组（每组n=6）：溶剂组（0.5% CMC-Na）、普伐他汀钠（Pravastatin sodium） 1 mg/kg/天组、5 mg/kg/天组、10 mg/kg/天组[1]
- 处理：每日口服灌胃，持续21天（期间继续饲喂HCD）；第21天采集禁食血清[1]
- 结果：
- 血清低密度脂蛋白胆固醇（LDL-C）：较溶剂组（290±35 mg/dL）分别降低28%（1 mg/kg）、42%（5 mg/kg）、55%（10 mg/kg）；
- 血清总胆固醇（TC）：较溶剂组（380±40 mg/dL）分别降低22%（1 mg/kg）、35%（5 mg/kg）、48%（10 mg/kg）；
- 血清高密度脂蛋白胆固醇（HDL-C）：5 mg/kg和10 mg/kg组较溶剂组分别升高8%和12%[1]
2. HCD喂养的新西兰白兔（2~3 kg）：
- 口服普伐他汀钠（Pravastatin sodium） 10 mg/kg/天，持续28天，血清LDL-C降低52%，TC降低45%[1]
- 妊娠期高血压（GH）大鼠模型的疗效：
1. 动物：妊娠第10天的SD大鼠随机分为3组（每组n=8）：正常对照组、GH+溶剂组、GH+普伐他汀钠（Pravastatin sodium） 组[2]
2. GH诱导：妊娠第10天至20天，通过皮下植入渗透泵输注Ang II（200 ng/kg/min）诱导GH[2]
3. 处理：普伐他汀钠 （5 mg/kg/天，溶于0.5% CMC-Na）从妊娠第10天至20天口服灌胃；溶剂组给予0.5% CMC-Na[2]
4. 结果：
- 血压：GH+普伐他汀钠 组妊娠第20天收缩压（SBP）从GH+溶剂组的165±10 mmHg降至135±8 mmHg；
- 血管舒张：胸主动脉内皮依赖的血管舒张功能（对乙酰胆碱的反应）较GH+溶剂组改善50%（血管环张力实验）；
- 氧化应激：血清丙二醛（MDA）水平较GH+溶剂组降低40%；
- MMP-2活性：主动脉MMP-2活性较GH+溶剂组降低45%（明胶酶谱法）[2]

血浆脂质过氧化水平的测定[2]
脂质过氧化产物采用硫代巴比妥酸（TBA）反应物质（TBARS）法，检测脂质过氧化的主要产物丙二醛（MDA）水平。简单地说，将100µL血浆加入试管中，与100µL蒸馏水、50µL 8.1%十二烷基硫酸钠（SDS）、375µL 20%乙酸和375µL 0.8% TBA在95°C水浴中孵育1小时。然后，将样品以4000 rpm离心10 min。将TBA加入样品中，立即得到比色反应，如前所述，通过532 nm波长测量。血浆MDA水平以nmol/mL表示。

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血浆抗氧化能力的测定[2]
如前所述，测定血浆的Trolox等效抗氧化能力（TEAC）。简单地说，用100 μg Trolox（6-羟-2,5,7,8-四甲基铬-2-羧酸）在1 mL醋酸钠缓冲液（0.4 M, C2H3NaO2.3H2O）和冰醋酸（0.4 M）中建立标准曲线，将血浆样品（20 μL）加入醋酸钠缓冲液和冰醋酸（200 μL）溶液中，在660 nm处读取吸光度。然后，用20 μL醋酸钠缓冲液（0.03 M）和冰醋酸（0.03 M）溶液（H2O2）和ABTS(2,2′-氮基-双（3-乙基苯-噻唑啉-6磺酸）；将Sigma， St. Louis， MO， USA)加入到样品中并孵育5分钟。然后，在分光光度计中进行第二次读取（660 nm）。用第一次读数的值减去第二次读数的值，样品的抗氧化活性用mmol Trolox当量/L表示。

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MMP-2酶谱分析[2]
如前所述，明胶酶谱法在胎盘中进行。简单地说，胎盘样品是用RIPA缓冲液（1 mM 1,10-邻菲罗啉，1 mM苯甲磺酰氟）和1 mM n -乙基马来酰亚胺制备的；含有蛋白酶抑制剂（4-（2-氨基乙基）苯磺酰氟（AEBSF）， E-64，贝司他汀，白细胞介素，抑蛋白蛋白和EDTA）。样品均质，用Bradford法测定蛋白质浓度。采用12%丙烯酰胺凝胶与明胶（0.05%）共聚，5μg胎盘蛋白电泳分离蛋白。在Triton X-100（2%）溶液中，在室温下洗涤两次，洗涤30分钟，在Tris-HCl缓冲液中孵育18小时，缓冲液中含有10 mmol/L CaCl2， pH为7.4。用考马斯亮蓝G-250对凝胶染色，用甲醇溶液对未染色的凝胶染色。采用ImageJ软件测定明胶水解活性。

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纯化人肝HMG-CoA还原酶活性检测：
反应体系（300 μL）包含50 mM Tris-HCl（pH 7.4）、5 mM MgCl2、2 mM二硫苏糖醇（DTT）、80 μg纯化人肝HMG-CoA还原酶、20 μM [14C]-HMG-CoA（底物，比活度50 Ci/mmol）、250 μM NADPH（辅酶）及普伐他汀钠（Pravastatin sodium） （0.01~50 μM）。混合物37°C孵育60分钟，使HMG-CoA转化为甲羟戊酸。加入100 μL 6 M HCl终止反应，95°C加热15分钟将甲羟戊酸转化为更易溶于有机溶剂的甲羟戊酸内酯。用600 μL乙酸乙酯提取甲羟戊酸内酯，取有机相至闪烁瓶，氮气吹干溶剂后加入1 mL闪烁液，液体闪烁计数器检测放射性。通过药物处理组与溶剂组的放射性比较计算抑制率，非线性回归拟合浓度-抑制曲线得IC50[1]

血管反应性[2]
解剖腹主动脉段，切成4个环（3mm），其中2个环机械去除内皮，2个环保留内皮。每个主动脉环挂在两个钢丝钩之间，放入含有Krebs-Henseleit溶液(NaCl 130；氯化钾4.7;氯化钙1.6;KH2PO4 1.2;MgSO4 1.2;NaHCO3 15;葡萄糖11.1;（mmol/L）在pH 7.4和37℃条件下，用95% O2和5% CO2起泡，然后在1.5 g的基张力下稳定。[2]
在主动脉环平衡后，通过给药KCl （96 mM）获得KCl最大收缩量，以检测主动脉活力。为了检测内皮功能，用10−6 M的苯肾上腺素（Phe）预收缩主动脉环，并增加浓度（10−9至10−4 M）的乙酰胆碱（ACh）。为了证实内皮源性no依赖性血管舒张的参与，在与Phe预收缩的主动脉环中，在n ω-硝基- l -精氨酸甲酯（L-NAME, 3 × 10−4 M）存在的情况下，获得了对ACh的浓度响应曲线。对得到的浓度-效应曲线进行非线性回归（变斜率），得到了Rmax（最大反应）和pEC50（引起最大反应50%的浓度的负对数）。松弛曲线用松弛对ph诱导收缩的百分比表示，如前所述。[2]

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人肝细胞胆固醇合成实验：
1. 细胞培养：从正常肝组织分离原代人肝细胞，以1.5×105细胞/孔接种6孔板，用含10% FBS、100 U/mL青霉素和100 μg/mL链霉素的William’s E培养基，37°C、5% CO2培养48小时，使细胞贴壁稳定[1]
2. 药物处理：更换为含普伐他汀钠（Pravastatin sodium） （0.1 μM、1 μM、10 μM、20 μM）或溶剂（0.1% DMSO）的无血清William’s E培养基，预孵育1小时后，每孔加入2 μCi/mL [14C]-乙酸（胆固醇合成前体），继续孵育24小时[1]
3. 胆固醇提取与定量：细胞用冰浴PBS洗涤2次，0.5 mL 0.1 M NaOH裂解。加入1 mL氯仿:甲醇（2:1，v/v）提取脂质，涡旋后1500×g离心10分钟。收集有机相，氮气吹干后用100 μL氯仿重悬，点样于薄层色谱（TLC）板，以正己烷:乙醚:乙酸（80:20:1，v/v/v）展开。碘蒸气显色定位胆固醇条带，刮取条带至闪烁瓶，液体闪烁计数法定量新生胆固醇合成量[1]
- HUVEC功能与氧化应激/MMP-2实验：
1. 细胞培养：从人脐静脉分离HUVECs，用含10% FBS、内皮细胞生长因子及抗生素的内皮细胞生长培养基（ECGM）培养，使用3~5代细胞[2]
2. 药物与刺激处理：HUVECs以2×105细胞/孔（6孔板）或5×103细胞/孔（96孔板）接种至80%融合。普伐他汀钠（Pravastatin sodium） （0.1 μM、1 μM、10 μM）预处理24小时后，用Ang II（100 nM）刺激6小时（检测ROS/NO）或24小时（检测MMP-2）[2]
3. NO检测：通过Griess试剂检测NO的稳定代谢产物亚硝酸盐。收集上清液，与等体积Griess试剂（5%磷酸中的1%磺胺和0.1% N-（1-萘基）乙二胺二盐酸盐）混合，室温孵育15分钟，检测540 nm吸光度，用亚硝酸钠标准曲线计算NO浓度[2]
4. ROS检测：细胞负载10 μM DCFH-DA 30分钟（37°C），PBS洗涤后加入Ang II刺激，酶标仪检测荧光强度（激发488 nm，发射525 nm）评估ROS水平[2]
5. MMP-2活性与表达：明胶酶谱法检测MMP-2活性：上清液与非还原样本缓冲液混合，上样至含0.1%明胶的10% SDS-PAGE凝胶电泳，凝胶复性后在发育缓冲液中孵育，考马斯亮蓝染色并脱色，透明条带代表MMP-2活性；Western blot用抗MMP-2抗体检测其蛋白表达[2]

Dissolved in water; 30 mg/kg/day; oral administration
Male Wistar rats receiving irradiation for 5 weeks 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]

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HCD-induced hypercholesterolemic SD rat study :
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]
2. 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]
3. Grouping: Selected rats were randomized into 4 groups (n=6/group):
- Vehicle group: 0.5% carboxymethyl cellulose sodium (CMC-Na) solution;
- Pravastatin sodium 1 mg/kg/day group;
- Pravastatin sodium 5 mg/kg/day group;
- Pravastatin sodium 10 mg/kg/day group [1]
4. Drug preparation: Pravastatin sodium was dissolved in 0.5% CMC-Na, sonicated for 5 minutes to form a homogeneous suspension (no precipitation observed) [1]
5. 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]
6. 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]
- Gestational hypertension rat study :
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]
2. 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]
3. Grouping: Pregnant rats with GH (SBP > 150 mmHg on gestational day 14) were randomized into 2 groups (n=8/group):
- GH + Vehicle group: 0.5% CMC-Na solution;
- GH + Pravastatin sodium group: 5 mg/kg/day [2]
4. 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]
5. Sample collection and detection:
- Blood pressure: SBP was measured using a non-invasive tail-cuff method on gestational days 10, 14, and 20;
- 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;
- 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 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. ...

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Oral absorption :
- Healthy volunteers: Single oral dose of Pravastatin sodium 40 mg (tablet) showed oral bioavailability (F) = 18% (higher than other lipophilic statins due to lower first-pass metabolism); time to reach maximum concentration (Tmax) = 1–2 hours; maximum plasma concentration (Cmax) = 20–30 ng/mL [1]
- Food effect: High-fat meal increased oral bioavailability by 20% (due to improved solubility), unlike lipophilic statins (e.g., lovastatin) where food reduces absorption [1]
- Distribution :
- Volume of distribution (Vd) = 13–16 L (healthy volunteers, oral 40 mg);
- Tissue distribution: High concentration in the liver (target organ, liver/plasma concentration ratio = 200:1); minimal penetration into the central nervous system (CNS, brain/plasma concentration ratio < 0.01) due to high water solubility [1]
- Metabolism :
- Minimally metabolized in the liver: Only 20% of the dose is metabolized, primarily via glucuronidation (not dependent on cytochrome P450 enzymes, especially CYP3A4), reducing the risk of drug-drug interactions [1]
- Elimination :
- Elimination half-life (t1/2) = 1.5–2 hours (healthy volunteers);
- Excretion: 70% of the dose is excreted via feces (40% as unchanged drug, 30% as glucuronide metabolites), 30% via urine (20% as unchanged drug, 10% as metabolites) [1]

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 lifexstyle 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\tman\tTDLo\toral\t16 mg/kg/8W-I\tLIVER: JAUNDICE, CHOLESTATIC; LIVER: LIVER FUNCTION TESTS IMPAIRED; SKIN AND APPENDAGES (SKIN): DERMATITIS, OTHER: AFTER SYSTEMIC EXPOSURE\tAmerican Journal of Emergency Medicine., 17(1388), 1999
16759173\twomen\tTDLo\toral\t16800 ug/kg\tBEHAVIORAL: SOMNOLENCE (GENERAL DEPRESSED ACTIVITY)\tLancet., 340(910), 1992
16759173\twomen\tTDLo\toral\t30 mg/kg/21W-I\tBEHAVIORAL: MUSCLE WEAKNESS; BLOOD: CHANGES IN SERUM COMPOSITION (E.G., TP, BILIRUBIN, CHOLESTEROL); SKIN AND APPENDAGES (SKIN): DERMATITIS, OTHER: AFTER SYSTEMIC EXPOSURE\tNew England Journal of Medicine., 327(649), 1992
16759173\trat\tLD50\toral\t>12 gm/kg\t\tYakkyoku. Pharmacy., 40(2351), 1989
16759173\trat\tLD50\tsubcutaneous\t3172 mg/kg\tBEHAVIORAL: ATAXIA; LUNGS, THORAX, OR RESPIRATION: OTHER CHANGES; SKIN AND APPENDAGES (SKIN): HAIR: OTHER\tYakuri to Chiryo. Pharmacology and Therapeutics., 15(4949), 1987

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In vitro cytotoxicity (Literature [1], [2]):
- Primary human hepatocytes: Pravastatin sodium (up to 100 μM, 72-hour treatment) showed no significant cytotoxicity, with cell viability > 90% compared to the vehicle group (MTT assay) [1]
- HUVECs: Pravastatin sodium (up to 20 μM, 48-hour treatment) had no adverse effect on cell viability (> 95% viability) [2]
- In vivo safety (Literature [1], [2]):
- HCD-fed SD rats (10 mg/kg/day, 21 days):
- No significant changes in body weight (weight change < 4% vs. vehicle);
- Serum liver function markers (alanine transaminase [ALT], aspartate transaminase [AST]) were slightly increased (1.2-fold vs. vehicle, within the normal reference range);
- Serum creatinine and blood urea nitrogen (BUN, kidney function markers) remained normal [1]
- Pregnant GH rats (5 mg/kg/day, 10 days):
- No fetal toxicity: Fetal weight, litter size, and fetal malformation rate were comparable to the normal control group;
- No maternal organ damage: Liver and kidney histopathology showed no abnormal changes [2]
- Plasma protein binding :
- Human plasma: Protein binding rate = 50–55% (equilibrium dialysis method, 37°C, pH 7.4), which is 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 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).

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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. It was first approved for clinical use in 1989 for the treatment of hypercholesterolemia [1]
- Core mechanisms:
- Lipid-lowering: Inhibits HMG-CoA reductase to block mevalonate synthesis (a key intermediate in cholesterol biosynthesis), thereby reducing hepatic de novo cholesterol production and upregulating hepatic LDL receptors to enhance LDL-C clearance from the bloodstream [1]
- Pleiotropic effects (beyond lipid lowering): Improves endothelial function by promoting NO production, reduces oxidative stress (via inhibiting ROS generation), and suppresses 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., due to diabetes mellitus, hypothyroidism);
- Prevention of atherosclerotic cardiovascular diseases (ASCVD) such as myocardial infarction and stroke in patients with hypercholesterolemia [1]
- Clinical advantages (Literature [1], [2]):
- Water solubility: Minimal CNS penetration, reducing the risk of CNS-related adverse effects (e.g., headache, dizziness);
- Non-reliance on CYP3A4 metabolism: Lower risk of drug-drug interactions with CYP3A4 substrates (e.g., erythromycin, cyclosporine);
- Safety in special populations: Shown to be safe in pregnant rats (in the GH model) and has a favorable safety profile 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

124.29

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

注意： 请将本产品存放在密封且受保护的环境中（例如氮气保护），避免吸湿/受潮和光照。

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

配方 1 中的溶解度: ≥ 2.5 mg/mL (5.60 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (5.60 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.5 mg/mL (5.60 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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配方 4 中的溶解度: 100 mg/mL (223.96 mM) in PBS (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液; 超声助溶.

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。