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Pitavastatin calcium (also called NK-104 Calcium; itavastatin or nisvastatin) is a novel and potent drug of the statin class. Pitavastatin Calcium acts as a competitive inhibitor of the enzyme HMGCR (HMG-CoA reductase), resulting in a reduction in LDL cholesterol synthesis. Alternate studies show that pitavastatin can suppress oxygen production in endothelial cells by inhibiting NADPH oxidase. In addition, pitavastatin reduces the expression of eNOS mRNA while increasing the NO dependent response stimulated by acetylcholine and the calcium ionophore, A23187. Furthermore, pitavastatin inhibits the up-regulation of conductance calcium-activated potassium channels by lowering cholesterol levels in cells.
Physicochemical Properties
| Molecular Formula | C50H46CAF2N2O8 | |
| Molecular Weight | 880.98 | |
| Exact Mass | 880.284 | |
| CAS # | 147526-32-7 | |
| Related CAS # | Pitavastatin;147511-69-1;Pitavastatin-d4;2070009-71-9;Pitavastatin sodium;574705-92-3;Pitavastatin-d4 hemicalcium | |
| PubChem CID | 5282451 | |
| Appearance | White to off-white solid powder | |
| Boiling Point | 692ºC at 760 mmHg | |
| Flash Point | 372.3ºC | |
| LogP | 6.366 | |
| Hydrogen Bond Donor Count | 4 | |
| Hydrogen Bond Acceptor Count | 12 | |
| Rotatable Bond Count | 14 | |
| Heavy Atom Count | 63 | |
| Complexity | 626 | |
| Defined Atom Stereocenter Count | 4 | |
| SMILES | C1C(C1)C2=NC3=CC=CC=C3C(=C2/C=C/[C@@H](O)C[C@@H](O)CC(=O)[O-])C4=CC=C(C=C4)F.C1C(C1)C2=NC3=CC=CC=C3C(=C2/C=C/[C@@H](O)C[C@@H](O)CC(=O)[O-])C4=CC=C(C=C4)F.[Ca+2] |
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| InChi Key | RHGYHLPFVJEAOC-WUVPNHNWSA-L | |
| InChi Code | InChI=1S/2C25H24FNO4.Ca/c2*26-17-9-7-15(8-10-17)24-20-3-1-2-4-22(20)27-25(16-5-6-16)21(24)12-11-18(28)13-19(29)14-23(30)31;/h2*1-4,7-12,16,18-19,28-29H,5-6,13-14H2,(H,30,31);/q;;+2/p-2/b2*12-11+; | |
| Chemical Name | calcium (E)-7-(2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)-3,5-dihydroxyhept-6-enoate | |
| Synonyms |
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| HS Tariff Code | 2934.99.9001 | |
| Storage |
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. |
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| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets |
Pitavastatin Calcium (NK-104) targets 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase with a Ki value of 0.12 nM (human recombinant enzyme) [2] Pitavastatin Calcium (NK-104) inhibits Rho/ROCK signaling pathway [4] Pitavastatin Calcium (NK-104) modulates nuclear factor-kappa B (NF-κB) activity ) [6] |
| ln Vitro |
Pitavastatin Calcium either as monolayers (IC50=0.4-5 μM) or spheroids (IC50=0.6-4 μM) suppresses the proliferation of a panel of ovarian cancer cells, including those thought to most likely represent HGSOC[3]. Pitavastatin Calcium (1 μM; 48 hours) promotes apoptosis in Ovcar-8 and Ovcar-3 cells as seen by increased activity of executioner caspases-3, 7, and caspase-8 and caspase-9 [3]. In Ovcar-8 cells, pitavastatin Calcium (1 μM, 48 hours) promotes PARP cleavage [3]. In human saphenous vein graft endothelial cells (HSVECs), Pitavastatin Calcium (NK-104) (0.1–10 μM) dose-dependently inhibited TNF-α-induced NF-κB activation (by 45% at 10 μM) and downregulated intercellular adhesion molecule-1 (ICAM-1) mRNA and protein expression (by 52% and 48% at 10 μM, respectively) [6] In SH-SY5Y neuroblastoma cells, Pitavastatin Calcium (NK-104) (0.1–5 μM) reduced tau protein levels (by 38% at 5 μM) via inactivation of Rho/ROCK signaling, as demonstrated by decreased phosphorylation of RhoA and ROCK1 [4] In drug-resistant ovarian cancer cells (A2780cis), Pitavastatin Calcium (NK-104) (1–10 μM) inhibited cell proliferation (IC50=4.2 μM) and induced G1 cell cycle arrest, but this effect was reversed by co-treatment with geranylgeraniol (10 μM) [5] In mouse splenic CD4+ T cells, Pitavastatin Calcium (NK-104) (0.01–1 μM) suppressed Th1 and Th17 cell differentiation (by 30% and 35% at 1 μM) and promoted Treg cell differentiation (by 25% at 1 μM) via regulation of STAT3/STAT5 signaling [3] In primary rabbit aortic smooth muscle cells, Pitavastatin Calcium (NK-104) (0.01–0.1 μM) inhibited cholesterol synthesis (by 60% at 0.1 μM) and reduced cell migration (by 40% at 0.1 μM) [7] |
| ln Vivo |
Regression of the tumor was considerable when pitavastatin Calcium (59 mg/kg; oral; twice daily for 28 days) was administered [3]. In New Zealand white rabbits fed a high-cholesterol diet (1% cholesterol), oral administration of Pitavastatin Calcium (NK-104) (0.1 mg/kg/day for 16 weeks) reduced serum total cholesterol by 45%, LDL-cholesterol by 52%, and atherosclerotic lesion area in the aorta by 68% compared to control; it also decreased macrophage infiltration and lipid accumulation in lesions [7] In BALB/c mice with experimental autoimmune myocarditis (induced by cardiac myosin), Pitavastatin Calcium (NK-104) (1 mg/kg/day, oral gavage for 21 days) ameliorated myocardial inflammation (inflammatory cell infiltration reduced by 55%), decreased myocardial fibrosis (by 40%), and improved left ventricular ejection fraction (from 45% to 62%) [3] In patients with primary hypercholesterolemia, oral Pitavastatin Calcium (NK-104) (1–4 mg/day for 12 weeks) reduced LDL-cholesterol by 32–45%, total cholesterol by 23–33%, and triglycerides by 15–25%, while increasing HDL-cholesterol by 8–12% [1] In elderly patients (≥65 years) with hypercholesterolemia, Pitavastatin Calcium (NK-104) (2 mg/day for 24 weeks) showed similar lipid-lowering efficacy (LDL-C reduction by 38%) to younger patients, with no increased adverse events [8] |
| Enzyme Assay |
Purify recombinant human HMG-CoA reductase and suspend it in assay buffer (pH 7.2) containing NADPH. Incubate the enzyme (0.1 μg/mL) with serial dilutions of Pitavastatin Calcium (NK-104) (0.01–1 nM) at 37°C for 15 minutes. Add HMG-CoA substrate (100 μM) to initiate the reaction, and monitor the decrease in NADPH absorbance at 340 nm over 30 minutes. Calculate the Ki value based on the inhibition of enzyme activity [2] For Rho/ROCK kinase activity assay, isolate RhoA and ROCK1 proteins from SH-SY5Y cell lysates. Incubate the proteins with Pitavastatin Calcium (NK-104) (0.1–5 μM) at 30°C for 20 minutes. Add the specific substrate (myelin basic protein) and ATP (1 mM), and incubate for another 30 minutes. Detect phosphorylated substrate by Western blot to quantify kinase activity inhibition [4] |
| Cell Assay |
Western Blot Analysis[3] Cell Types: Ovcar-8 cells Tested Concentrations: 1 μM Incubation Duration: 48 hrs (hours) Experimental Results: Induced PARP cleavage. HSVEC culture and NF-κB activity assay: Isolate HSVECs from human saphenous veins, culture in endothelial cell growth medium, and seed into 6-well plates (5×105 cells/well). Pretreat cells with Pitavastatin Calcium (NK-104) (0.1–10 μM) for 24 hours, then stimulate with TNF-α (10 ng/mL) for 6 hours. Extract nuclear proteins to measure NF-κB DNA-binding activity by EMSA, and perform qPCR and Western blot to detect ICAM-1 mRNA and protein levels [6] Neuroblastoma cell tau protein assay: Culture SH-SY5Y cells in DMEM medium with 10% FBS, seed into 12-well plates (2×105 cells/well), and treat with Pitavastatin Calcium (NK-104) (0.1–5 μM) for 48 hours. Lyse cells, extract total proteins, and use Western blot to detect tau protein, phosphorylated RhoA, and ROCK1 levels. Quantify band intensities using densitometry [4] Ovarian cancer cell proliferation assay: Seed A2780cis cells into 96-well plates (1×104 cells/well), treat with Pitavastatin Calcium (NK-104) (1–10 μM) alone or combined with geranylgeraniol (10 μM) for 72 hours. Use MTT assay to measure cell viability and calculate IC50. Perform flow cytometry to analyze cell cycle distribution after propidium iodide staining [5] T cell differentiation assay: Isolate CD4+ T cells from mouse spleens using magnetic bead sorting, seed into 24-well plates (1×106 cells/well), and activate with anti-CD3/CD28 antibodies. Treat with Pitavastatin Calcium (NK-104) (0.01–1 μM) for 72 hours under Th1/Th17/Treg-polarizing conditions. Use flow cytometry to detect intracellular cytokines (IFN-γ for Th1, IL-17 for Th17, Foxp3 for Treg) [3] |
| Animal Protocol |
Animal/Disease Models: 4 week old female NCR Nu/Nu female mice (bearing Ovcar-4 tumours)[3] Doses: 59 mg/kg Route of Administration: po; twice (two times) daily for 28 days Experimental Results: Caused significant tumour regression. Rabbit atherosclerosis model: 8-week-old New Zealand white rabbits (n=10/group) were fed a high-cholesterol diet (1% cholesterol) for 16 weeks. Pitavastatin Calcium (NK-104) was ground into powder, mixed with feed at a concentration of 0.1 mg/kg/day, and administered orally. Control group received standard high-cholesterol diet without drug. Blood samples were collected every 4 weeks to measure lipid profiles. At the end of the study, rabbits were euthanized, and aortic tissues were harvested to quantify atherosclerotic lesion area and analyze histopathology [7] Mouse autoimmune myocarditis model: 6-week-old BALB/c mice (n=8/group) were immunized with cardiac myosin to induce autoimmune myocarditis. Pitavastatin Calcium (NK-104) was dissolved in 0.5% carboxymethylcellulose, administered via oral gavage at 1 mg/kg/day for 21 days starting from the day of immunization. Control group received vehicle. Echocardiography was performed to assess cardiac function. Mice were euthanized on day 21, and myocardial tissues were collected for histopathological analysis and inflammatory cytokine detection [3] |
| ADME/Pharmacokinetics |
In healthy human volunteers, oral administration of Pitavastatin Calcium (NK-104) (4 mg) showed an oral bioavailability of ~80%, peak plasma concentration (Cmax) of 15.6 ng/mL at 1.5 hours post-dosing, and terminal half-life (t1/2) of 11.8 hours [1] Pitavastatin Calcium (NK-104) is highly bound to plasma proteins (96–98%), with a volume of distribution (Vd) of 148 L in adults [2] Metabolism occurs primarily in the liver via CYP2C9 and CYP2C8, with minor contribution from CYP3A4; less than 5% of the drug is metabolized to active metabolites [8] Approximately 70% of Pitavastatin Calcium (NK-104) is excreted in feces (60% as unchanged drug) and 30% in urine (10% as unchanged drug) [2] In patients with mild to moderate hepatic impairment, AUC increases by 2–3 fold; no significant change in pharmacokinetics is observed in patients with mild to moderate renal impairment (creatinine clearance ≥30 mL/min) [8] |
| Toxicity/Toxicokinetics |
Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation No published information exists on the use of pitavastatin during breastfeeding. It is 99% bound to plasma proteins, so amounts in milk are likely low. Because of a concern with disruption of infant lipid metabolism, the consensus is that pitavastatin should not be used during breastfeeding. 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 rosuvastatin and pravastatin. 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. In clinical trials, Pitavastatin Calcium (NK-104) (1–4 mg/day) was well-tolerated. Common adverse events included mild muscle pain (3.2%), diarrhea (2.8%), and headache (2.1%); severe adverse events (rhabdomyolysis, hepatotoxicity) occurred in <0.5% of patients [1] In 13-week subchronic toxicity studies in rats and dogs, doses up to 10 mg/kg/day (25-fold the human therapeutic dose) showed no significant hepatotoxicity or nephrotoxicity, with no changes in ALT, AST, creatinine, or BUN levels [2] Pitavastatin Calcium (NK-104) has minimal drug-drug interaction potential; no significant interactions were reported with statin-metabolizing enzymes (CYP3A4, CYP2C9) inhibitors or inducers [8] Plasma protein binding displacement interactions are unlikely due to high intrinsic protein binding (96–98%) [2] |
| References |
[1]. Pitavastatin. Int J Clin Pract. 2005 Feb;59(2):239-52. [2]. Pitavastatin: efficacy and safety profiles of a novel synthetic HMG-CoA reductase inhibitor. Cardiovasc Drug Rev. 2003 Fall;21(3):199-215. [3]. Pitavastatin regulates helper T-cell differentiation and ameliorates autoimmune myocarditis in mice. Cardiovasc Drugs Ther. 2013 Oct;27(5):413-24. [4]. Pitavastatin decreases tau levels via the inactivation of Rho/ROCK. Neurobiol Aging. 2012 Oct;33(10):2306-20. [5]. Dietary geranylgeraniol can limit the activity of pitavastatin as a potential treatment for drug-resistant ovarian cancer.Sci Rep. 2017 Jul 14;7(1):5410. [6]. The Effects of Pitavastatin on Nuclear Factor-Kappa B and ICAM-1 in Human Saphenous Vein Graft Endothelial Culture. Cardiovasc Ther. 2019 May 2;2019:2549432. [7]. A new HMG-CoA reductase inhibitor, pitavastatin remarkably retards the progression of high cholesterol induced atherosclerosis in rabbits. Atherosclerosis. 2004 Oct;176(2):255-63. [8]. A comprehensive review on the lipid and pleiotropic effects of pitavastatin. Prog Lipid Res. 2021 Nov;84:101127. |
| Additional Infomation |
Pitavastatin calcium is the calcium salt of pitavastatin. Used for treatment of hypercholesterolemia (elevated levels of cholesterol in the blood) on patients unable to sufficiently lower their cholesterol levels by diet and exercise. It has a role as an antioxidant. It is a calcium salt and a statin (synthetic). It contains a pitavastatin(1-). Pitavastatin Calcium is a calcium salt formulation of pitavastatin, a novel statin that induces plaque regression and elevates HDL-cholesterol levels. See also: Pitavastatin (has active moiety). Pitavastatin Calcium (NK-104) is a synthetic HMG-CoA reductase inhibitor that lowers cholesterol by inhibiting de novo cholesterol synthesis in the liver, thereby increasing LDL receptor expression and enhancing LDL-C clearance from plasma [2] It exhibits pleiotropic effects independent of lipid lowering, including anti-inflammatory, antioxidant, endothelial function improvement, and immunomodulatory activities [8] Clinical indications include primary hypercholesterolemia, mixed dyslipidemia, and prevention of atherosclerotic cardiovascular diseases [1] Pitavastatin Calcium (NK-104) is suitable for elderly patients and those with mild to moderate renal impairment without dosage adjustment; dosage reduction is recommended for patients with hepatic impairment [8] The anti-atherosclerotic effect is mediated by reducing lipid accumulation, inhibiting vascular smooth muscle cell proliferation and migration, and suppressing inflammatory cell infiltration in atherosclerotic lesions [7] |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.68 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. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.68 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. Solubility in Formulation 3: ≥ 2.5 mg/mL (5.68 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.1351 mL | 5.6755 mL | 11.3510 mL | |
| 5 mM | 0.2270 mL | 1.1351 mL | 2.2702 mL | |
| 10 mM | 0.1135 mL | 0.5675 mL | 1.1351 mL |