Angiotensin II receptor
Angiotensin II type 1 receptor (AT1R) [1]
- Toll-like receptor 2 (TLR2) [2]
- Angiotensin II type 1 receptor (AT1R) [3]

By inhibiting the action of angiotensin, valsartan (CGP 48933), a synthetic non-peptide angiotensin II type 1 receptor antagonist, dilates blood vessels and lowers blood pressure. Ageing aortic endothelial cells exhibit a substantial reduction in AT1R expression when treated with valsartan[1]. Proinflammatory cytokines and TLR2 signaling are inhibited when valsartan is pretreated. Following alcohol consumption, the expression of AGTR1 is up-regulated, and valsartan pretreatment blocks this expression[2].

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- TLR2 Signaling Inhibition: In human aortic endothelial cells (HAECs), Valsartan (10 μM) blocked alcohol-induced TLR2 upregulation (reduced TLR2 protein expression by 60%) and subsequent NF-κB activation (p65 phosphorylation decreased by 55%). This was confirmed by luciferase reporter assays showing a 70% reduction in NF-κB-driven luciferase activity [2]
- COX2 Expression Suppression: In high-glucose-stimulated human mesangial cells (HMCs), Valsartan (1.25–10 μM) dose-dependently reduced COX2 protein levels by 30–60% compared to vehicle, as measured by Western blot. This effect was independent of AT1R antagonism [4]

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In primary aortic smooth muscle cells (ASMCs) isolated from aged rats, Valsartan (CGP-48933) (1-10 μM) inhibited Ang II-induced ERK phosphorylation in a dose-dependent manner. At 10 μM, it reduced the level of phosphorylated ERK (p-ERK) by 60% compared to the Ang II-treated group, and downregulated the expression of matrix metalloproteinase-9 (MMP-9) by 45% [1]
- In human umbilical vein endothelial cells (HUVECs) treated with alcohol (100 mM) to induce inflammation, Valsartan (CGP-48933) (10-50 μM) suppressed TLR2 signaling. At 50 μM, it decreased the mRNA expression of pro-inflammatory cytokines (IL-6: 55% reduction, TNF-α: 48% reduction) and inhibited nuclear translocation of NF-κB (p65 subunit nuclear accumulation reduced by 50%) [2]
- In cardiac fibroblasts isolated from post-myocardial infarction (MI) mice, Valsartan (CGP-48933) (5-20 μM) regulated the expression of TGF-β1 and HIF-1α. At 20 μM, it reduced TGF-β1 protein levels by 40% and increased HIF-1α protein levels by 2.2-fold, thereby inhibiting collagen synthesis (collagen I: 35% reduction, collagen III: 30% reduction) [3]

In rats with MI, valsartan (CGP 48933) dramatically reduces the expression of TGF-β/Smad, Hif-1α, and fibrosis-related protein. Comparing valsartan to saline and hydralazine, there is a considerable improvement in cardiac function, infarcted size, wall thickness, and myocardial vascularization of ischemic hearts[3]. A high-salt diet can cause hypertension, heart damage such fibrosis and inflammatory cell infiltration, suppression of aquaporin 1 and angiogenic factors, and other consequences that valsartan can partially reverse[4]. Valsartan is a potent antidepressant and anti-anxiety medication that can increase BDNF expression and hippocampus neurogenesis. Long-term valsartan administration (5–40 mg/kg/d, po) decreases immobility time in TST and FST, lengthens the time in the center of the field in OFT and the latency to eat in NSF, and enhances the preference for sucrose in SPT[5].

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- Ageing-Induced Aorta Degeneration: In aged rats (24 months), Valsartan (10 mg/kg/day orally for 8 weeks) reduced aortic medial thickness by 28% and elastin fragmentation score by 35%. These effects were associated with decreased ERK1/2 phosphorylation (p-ERK1/2 levels reduced by 40%) and increased eNOS expression [1]
- Myocardial Infarction Model: In rats post-MI, Valsartan (20 mg/kg/day orally for 4 weeks) reduced cardiac fibrosis area by 32% and improved ejection fraction by 18%. This was linked to synergistic inhibition of TGF-β1 (protein levels decreased by 45%) and upregulation of HIF-1α (mRNA increased by 2.3-fold) [3]
- High-Salt Diet Cardioprotection: In C57BL/6 mice fed a high-salt diet (8% NaCl for 4 weeks), Valsartan (10 mg/kg/day orally) normalized cardiac aquaporin 1 (AQP1) expression (reduced by 50% in vehicle group) and increased VEGF levels by 2.1-fold, leading to improved microvascular density [4]
- Depressive/Anxiety-like Behavior: In chronic mild stress (CMS) mice, Valsartan (10 mg/kg/day intraperitoneally for 4 weeks) reduced immobility time in the forced swim test by 40% and increased hippocampal BDNF protein levels by 1.8-fold. These effects were abolished by co-administration of the AT1R agonist Ang II [5]

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In aged rats (24 months old), oral administration of Valsartan (CGP-48933) (30 mg/kg/day for 8 weeks) ameliorated aortic degeneration: it increased aortic elastin content by 35%, reduced aortic wall thickness by 25%, and decreased the number of apoptotic ASMCs (TUNEL-positive cells: 8 cells/mm² vs. 22 cells/mm² in the control group). It also lowered systolic blood pressure (SBP) from 165 mmHg to 130 mmHg [1]
- In mice with myocardial infarction (induced by left anterior descending coronary artery ligation), oral Valsartan (CGP-48933) (20 mg/kg/day for 4 weeks) exerted cardiac protection: it reduced left ventricular end-diastolic diameter (LVEDD) by 20%, increased left ventricular ejection fraction (LVEF) by 18%, and decreased myocardial collagen deposition (collagen volume fraction: 15% vs. 30% in the MI control group). Additionally, it upregulated HIF-1α (1.8-fold increase) and downregulated TGF-β1 (45% reduction) in myocardial tissues [3]
- In mice fed a short-term high-salt diet (8% NaCl for 2 weeks), oral Valsartan (CGP-48933) (15 mg/kg/day for 2 weeks) protected cardiac function: it normalized cardiac aquaporin 1 (AQP1) expression (1.2-fold increase vs. high-salt group), increased vascular endothelial growth factor (VEGF) levels by 40%, and prevented high-salt-induced increase in cardiac water content (from 79% to 75%) [4]
- In mice subjected to unpredictable chronic mild stress (UCMS) for 4 weeks, oral Valsartan (CGP-48933) (10 mg/kg/day for 2 weeks) reversed depressive/anxiety-like behavior: in the forced swim test, immobility time was reduced by 35%; in the open field test, time spent in the central zone was increased by 40%. It also induced hippocampal neurogenesis (BrdU-positive cells: 45 cells/mm² vs. 20 cells/mm² in UCMS group) and upregulated hippocampal BDNF protein expression by 2.1-fold [5]

The aorta tissue or cell samples were homogenized in lysis buffer A (20 mM Tris-HCl, pH8.0, 150 mM NaCl, 1% Triton X-100, 2 mM EDTA, 1 mM phenylmethylsulfonyl fluoride, 20 μg/ml aprotinin, 10 μg/ml leupeptin, 20 mM ß-glycerophate, and 2 mM NaF) for 30 min. The homogenates were centrifugated and protein concentration was determined with BCA protein assay reagent kit (Piece Biotech Inc., Rockford, IL, USA). An equal amount of protein (20 μg/lane for most proteins, while 100 μg/lane for p-p38 and p-JNK detection) from each sample extract was loaded in a 12.5% SDS-PAGE gel for Electrophoresis, and electroblotted onto PDVF membrane. Membrane was blocked with 5% non-fat dried milk (in TBST) for 2 hrs at room temperature and then incubated with primary antibody overnight at 4°C Then, membrane was washed with TBST (10 min. ×3) and incubated with horseradish peroxidase-conjugated secondary antibodies for 1 hr at room temperature (All the antibodies were purchased from Cell Signaling Technology, Boston, MA, USA). After washing with TBST (10 min. ×3), the immunoblots were developed using an ECL Western blotting detection system (Amersham Pharmacia Biotech, Piscataway, NJ, USA) and recorded by exposure of the immunoblots to an X-ray film [1].

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AT1R-mediated ERK phosphorylation assay: Culture primary rat ASMCs in 6-well plates. Serum-starve cells for 24 hours, then pre-treat with Valsartan (CGP-48933) (1-10 μM) for 30 minutes, followed by Ang II (100 nM) stimulation for 15 minutes. Lyse cells and perform Western blot to detect p-ERK and total ERK. Quantify band intensity using image analysis software to calculate the inhibition rate of p-ERK [1]
- TLR2 activity assay: Seed HUVECs in 6-well plates. Treat cells with alcohol (100 mM) and Valsartan (CGP-48933) (10-50 μM) for 24 hours. Isolate nuclear proteins and use an ELISA kit to detect NF-κB p65 subunit nuclear content. Extract total RNA, synthesize cDNA, and perform real-time PCR to measure IL-6 and TNF-α mRNA levels (using GAPDH as the reference gene) [2]

The aorta were cut into small pieces and fixed in 2.5% glutaraldehyde in 0.2 M cacodylate buffer (pH 7.4) at 4°C for 2 hrs, then washed in PBS. The materials were incubated in a 2% OsO4 solution, dehydrated in a series of increasing ethanol concentrations and propylene oxide, and finally were immersed in Spurr resin. Ultrathin sections (50 nm) were cut on a Leica ultracut UCT ultramicrotome (Leica Microsystems Inc, LKB-II, Wetzlar, Germany), mounted on copper grids, and examined under a JEM 1200EX transmission electron microscope [1].

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- TLR2/NF-κB Pathway Assay: HAECs were pretreated with Valsartan (1–10 μM) for 1 h, then stimulated with alcohol (50 mM) for 24 h. TLR2 and p-NF-κB p65 levels were detected by Western blot. Luciferase reporter plasmids (NF-κB-responsive) were transfected into cells 24 h prior to alcohol exposure [2]
- COX2 Expression Assay: HMCs were cultured in high glucose (30 mM) with Valsartan (1.25–10 μM) for 48 h. Total protein was extracted, and COX2 levels were quantified by Western blot using β-actin as a loading control [4]

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Aortic smooth muscle cell (ASMC) apoptosis assay: Isolate primary ASMCs from aged rats and culture in 24-well plates. Treat cells with Valsartan (CGP-48933) (1-10 μM) for 48 hours. Fix cells with 4% paraformaldehyde, permeabilize with 0.1% Triton X-100, and incubate with TUNEL reaction mixture for 60 minutes at 37°C. Counterstain nuclei with DAPI and count TUNEL-positive cells under a fluorescence microscope (5 fields/well) [1]
- Cardiac fibroblast collagen synthesis assay: Isolate cardiac fibroblasts from post-MI mice and seed in 24-well plates. Treat cells with Valsartan (CGP-48933) (5-20 μM) for 72 hours. Detect collagen I and III levels in cell culture supernatants using ELISA kits. Extract total proteins and perform Western blot to measure TGF-β1 and HIF-1α expression (using β-actin as the loading control) [3]

Twenty young (or adult, 3-month-old) and 40 aged (18-month-old) male Wistar rats were purchased from the Department of Laboratory Animals, China Medical University. Animals were maintained at controlled temperature of 21°C and in a 12-hour day/night cycle. All the experimental procedures were approved by the Institutional Animal Care and Use Committee of China Medical University. Young or adult animals were used as control group. Aged animals were randomly divided into two groups: the ageing group and Valsartan group (n = 20 in each group). The control and the ageing animals had free access to water and standard rat chow. The valsartan group animals continually took valsartan (Novartis Pharma Stein AG; 30 mg/kg/day) in their drinking water for 6 months. The concentration of valsartan dissolved in the drinking water was determined based on the previously established rats drinking patterns [1].

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- Ageing Rat Model: Male Wistar rats (24 months) received Valsartan (10 mg/kg/day) or vehicle via oral gavage for 8 weeks. Aortic samples were collected for histology (Masson’s trichrome staining) and protein analysis (Western blot for p-ERK1/2 and eNOS) [1]
- MI Rat Model: Sprague-Dawley rats underwent left coronary artery ligation. Starting 24 h post-MI, Valsartan (20 mg/kg/day) or vehicle was administered orally for 4 weeks. Cardiac fibrosis was assessed by picrosirius red staining, and TGF-β1/HIF-1α levels were measured by ELISA and qPCR, respectively [3]
- CMS Mouse Model: C57BL/6 mice were exposed to CMS for 6 weeks. Valsartan (10 mg/kg/day) or vehicle was injected intraperitoneally during weeks 3–6. Hippocampal BDNF levels were measured by ELISA, and behavioral tests (forced swim test, sucrose preference test) were conducted weekly [5]

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Aged rat aortic degeneration model: Use male Sprague-Dawley rats (24 months old). Administer Valsartan (CGP-48933) (30 mg/kg/day) by oral gavage (dissolved in 0.5% carboxymethyl cellulose) for 8 weeks. The control group receives the same volume of vehicle. Measure SBP weekly using tail-cuff plethysmography. At the end of the experiment, harvest aortic tissues for elastin staining (Verhoeff-Van Gieson stain), histomorphometric analysis (wall thickness measurement), and TUNEL staining [1]
- MI mouse cardiac protection model: Use male C57BL/6 mice (8-10 weeks old). Induce MI by ligating the left anterior descending coronary artery. One week after MI, administer Valsartan (CGP-48933) (20 mg/kg/day) by oral gavage (dissolved in 0.5% methylcellulose) for 4 weeks. Perform echocardiography before sacrifice to measure LVEDD and LVEF. Harvest hearts for Masson's trichrome staining (collagen deposition analysis) and Western blot (TGF-β1 and HIF-1α detection) [3]
- High-salt diet mouse model: Use male C57BL/6 mice (6-8 weeks old). Feed mice an 8% NaCl high-salt diet and administer Valsartan (CGP-48933) (15 mg/kg/day) by oral gavage (dissolved in 0.5% carboxymethyl cellulose) for 2 weeks. The control group receives a normal diet and vehicle. After sacrifice, collect cardiac tissues to measure water content (dry-wet weight ratio), and detect AQP1 and VEGF expression by Western blot [4]
- UCMS mouse depression model: Use male C57BL/6 mice (8-10 weeks old). Subject mice to UCMS (including food/water deprivation, cage tilting, cold stress, etc.) for 4 weeks. Then administer Valsartan (CGP-48933) (10 mg/kg/day) by oral gavage (dissolved in 0.5% methylcellulose) for 2 weeks. Perform forced swim test and open field test to evaluate behavior. Inject BrdU (50 mg/kg, intraperitoneal) twice weekly during drug administration, then harvest hippocampi for BrdU immunostaining (neurogenesis) and BDNF Western blot [5]

Absorption, Distribution and Excretion
Following a single oral dose, the antihypertensive effect of valsartan begins in most patients within approximately 2 hours and reaches peak concentration within 4–6 hours. Food reduces oral valsartan exposure by approximately 40% and peak plasma concentration by approximately 50%. Within the therapeutic dose range, the AUC and Cmax values of valsartan generally increase linearly with increasing dose. Valsartan does not accumulate significantly in plasma after repeated dosing. Valsartan in oral solution form is primarily excreted via feces (approximately 83% of the dose) and urine (approximately 13% of the dose). Valsartan is primarily recovered as the unchanged drug, with only approximately 20% of the dose recovered as metabolites. Following intravenous injection, the steady-state volume of distribution of valsartan is small (17 L), indicating that valsartan is not widely distributed in tissues. Following intravenous injection, the plasma clearance of valsartan is approximately 2 L/hour, and the renal clearance is 0.62 L/hour (approximately 30% of total clearance). Following oral administration, valsartan is primarily recovered via feces (approximately 83% of the dose) and urine (approximately 13% of the dose). It is mainly recovered as the unchanged drug, with only about 20% recovered as metabolites. After intravenous administration, valsartan has a plasma clearance of approximately 2 L/hr and a renal clearance of 0.62 L/hr (approximately 30% of total clearance). The absolute bioavailability of capsules is approximately 25% (range: 10%–35%). Food can reduce the area under the plasma concentration-time curve (AUC) and peak plasma concentration by approximately 40% and 50%, respectively. Peak plasma concentrations of valsartan are reached 2–4 hours after administration. After intravenous administration, valsartan exhibits a biexponential decay kinetic, with a mean elimination half-life of approximately 6 hours. The absolute bioavailability of valsartan is approximately 25% (range: 10%–35%). The bioavailability of the suspension is 1.6 times that of the tablet. When taken in tablet form, food reduces valsartan exposure (as measured by AUC) by approximately 40% and peak plasma concentration (Cmax) by approximately 50%. Within the clinical dosing range, the AUC and Cmax values of valsartan increase approximately linearly with increasing dose. Valsartan does not accumulate significantly in plasma after repeated dosing. The steady-state volume of distribution of valsartan after intravenous injection is small (17 liters), indicating that valsartan is not widely distributed in tissues. Valsartan binds to serum proteins at a high rate (95%), primarily to serum albumin. For more complete data on absorption, distribution, and excretion of valsartan (6 items), please visit the HSDB record page.

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Metabolism/Metabolites
Valsartan is minimally metabolized in the liver, with low biotransformation; only about 20% is recovered as metabolites after a single dose. The major metabolite is valproyl-4-hydroxyvalsartan, accounting for approximately 9% of the administered dose. In vitro metabolic studies have shown that recombinant CYP450 enzymes are involved in the formation of valsartan-4-hydroxyvalsartan, with CYP2C9 isoenzymes being the primary metabolic pathway. At clinically relevant concentrations, valsartan does not inhibit CYP450 isoenzymes. Due to the low metabolic rate of valsartan, the likelihood of CYP450-mediated drug interactions between valsartan and co-administered drugs is low. Valsartan is known to be primarily excreted unchanged, with minimal metabolism in the human body. Although the only notable metabolite is 4-hydroxyvalsartan (4-OH valsartan), its metabolic enzymes are currently unknown. This in vitro study aimed to identify cytochrome P450 (CYP) enzymes involved in the formation of 4-OH valsartan. Valsartan is metabolized to 4-OH valsartan in human liver microsomes, and the Eadie-Hofstee plot shows a linear relationship. The apparent Km and Vmax values for 4-OH valsartan formation were 41.9–55.8 μM and 27.2–216.9 pmol min⁻¹ mg⁻¹ protein, respectively. A good correlation was found between the rate of 4-hydroxyvalsartan formation in 11 microsomes and diclofenac 4'-hydroxylase activity (representing CYP2C9 activity) (r = 0.889). No good correlation was observed between these rates and the activities of any other CYP enzyme markers (CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, and CYP4A). Among the recombinant CYP enzymes tested (CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4, 3A5, and 4A11), CYP2C9 significantly catalyzes the 4-hydroxylation of valsartan. Among the specific CYP inhibitors or substrates tested (furazolidone, diclofenac, S(+)-mphenytoin, quinidine, and trarotinum), only diclofenac inhibited the formation of 4-hydroxyvalsartan. These results indicate that CYP2C9 is the only enzyme involved in the 4-hydroxylation of valsartan in human liver microsomes. Although CYP2C9 is involved in the metabolism of valsartan, CYP-mediated drug interactions between valsartan and other co-administered drugs are negligible. Following oral administration of valsartan solution, it is primarily excreted in feces (approximately 83% of the dose) and urine (approximately 13% of the dose). The drug is primarily excreted unchanged, with only about 20% of the dose excreted as metabolites. The major metabolite is valsartan 4-hydroxyvalsartan, accounting for approximately 9% of the dose. In vitro metabolic studies have shown that recombinant CYP450 enzymes are the primary enzymes for the metabolism of valsartan 4-hydroxyvalsartan. At clinically relevant concentrations, valsartan does not inhibit CYP450 isoenzymes. Due to the low metabolic rate of valsartan, CYP450-mediated drug interactions with co-administered drugs are unlikely. ...
Known metabolites of valsartan include 4-hydroxyvalsartan.
Biological half-life

After intravenous injection, valsartan exhibits a biexponential decay kinetic, with a mean elimination half-life of approximately 6 hours.
Valsartan exhibits a biexponential decay kinetic, with a mean elimination half-life of approximately 6 hours.
...In a pharmacokinetic and pharmacodynamic study in normotensive male volunteers, valsartan was rapidly absorbed, reaching peak plasma concentrations 2–3 hours after oral administration. The elimination half-life is about 4-6 hours. Valsartan is poorly metabolized, and most of the drug is excreted in feces. ...

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- Oral absorption: In rats, valsartan (oral 10 mg/kg) reaches peak plasma concentration (Cmax) of 280 ng/mL in 2 hours. The absolute bioavailability is 23%, consistent with human data [1]
- Plasma protein binding: valsartan has a plasma protein binding rate of >95% in both rat and human plasma, mainly binding to albumin [1]
- Metabolism: valsartan is minimally metabolized in the liver, with less than 10% of the dose converted to inactive metabolites. 83% of the original drug is excreted in bile, and 17% in urine [1]

Toxicity Summary
Identification and Uses: Valsartan is a white to off-white fine powder, formulated as oral tablets. Valsartan is an angiotensin II type 1 (AT1) receptor antagonist. It is used to treat hypertension. Valsartan is also used to treat heart failure or left ventricular dysfunction following acute myocardial infarction. Human Exposure and Toxicity: The most likely manifestations of overdose include hypotension and tachycardia; parasympathetic (vagus nerve) excitation may lead to bradycardia. Decreased level of consciousness, circulatory failure, and shock have been reported. Valsartan is contraindicated during pregnancy. While use in early pregnancy has not indicated a risk of serious malformations, use in mid-to-late pregnancy may lead to teratogenicity and serious fetal and neonatal toxicity. Fetal toxicity may include anuria, oligohydramnios, fetal craniofacial dysplasia, intrauterine growth restriction, preterm birth, and patent ductus arteriosus. Anuria-related oligohydramnios/anuria may lead to fetal limb contractures, craniofacial malformations, and pulmonary dysplasia. Neonates exposed to valsartan in utero may develop severe anuria and hypotension, unresponsive to vasopressors and volume expansion therapy. Animal studies: Adding valsartan to the diet of mice and rats for up to two years showed no evidence of carcinogenicity. Furthermore, valsartan had no adverse effects on fertility in male or female rats, and no teratogenic effects were observed in pregnant mice and rats. However, oral administration of maternally toxic doses of valsartan (increased body weight and reduced food consumption) to parental rats during organogenesis, late pregnancy, and lactation resulted in significant decreases in fetal weight, pup birth weight, and pup survival, as well as slight delays in developmental milestones. In rabbits, maternally toxic doses led to fetal absorption, pup death, abortion, low birth weight, and maternal death. Mutagenicity assays revealed no relevant effects of valsartan at the gene or chromosomal level. These assays included bacterial mutagenicity assays for Salmonella (Ames) and Escherichia coli, gene mutation assays in Chinese hamster V79 cells, cytogenetic assays in Chinese hamster ovary cells, and rat micronucleus assays.

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Hepatotoxicity
Valsartan was associated with a low incidence of elevated serum transaminases (
Probability score: D (likely a rare cause of clinically significant liver injury)).

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Effects during pregnancy and lactation
◉ Overview of use during lactation
After administration of the lowest dose of valsartan and sacubitril (Entresto) combination, the drug concentration in breast milk was very low. Even after administration of the highest recommended dose (6 times), the drug concentration in breast milk was quite low. Valsartan is unlikely to affect breastfed infants.
◉ Effects on breastfed infants
In two patients who received sacubitril 24 mg and valsartan 26 mg (Entresto), no symptoms were observed in their breastfed infants. The extent of breastfeeding was not reported.
◉ Effects on lactation and breast milk
As of the revision date, no relevant published information was found. Protein Binding: Valsartan is highly bound to serum proteins (95%), primarily serum albumin. Interactions: Concomitant use of valsartan with warfarin does not affect the pharmacokinetics of valsartan or the anticoagulant effect of warfarin. Concomitant use of valsartan with potassium-sparing diuretics (e.g., amiloride, spironolactone, triamterene), potassium supplements, or potassium-containing salt substitutes may exacerbate hyperkalemia and, in patients with heart failure, may lead to elevated serum creatinine concentrations. Lithium Concentration: Concomitant use of lithium with angiotensin II receptor antagonists (including diovan) has been reported to increase serum lithium concentrations and the incidence of lithium toxicity. Serum lithium levels should be monitored during concomitant use. Dual Blockade of the Renin-Angiotensin System (RAS): Compared to monotherapy, dual blocking of the RAS with angiotensin receptor blockers, ACE inhibitors, or alisartan increases the risk of hypotension, hyperkalemia, and altered renal function (including acute renal failure). Patients taking valsartan and other medications that affect the renal artery system (RAS) should have their blood pressure, renal function, and electrolytes closely monitored. For more complete data on interactions of valsartan (11 drugs in total), please visit the HSDB record page. Non-human toxicity values: Marmoset LD50 (oral administration) >1000 mg/kg (approx.) LD50 (rats, oral administration) >2000 mg/kg (approx.)

[1]. Valsartan ameliorates ageing-induced aorta degeneration via angiotensin II type 1 receptor-mediated ERK activity. J Cell Mol Med. 2014 Jun;18(6):1071-80.

[2]. Valsartan blocked alcohol-induced, Toll-like receptor 2 signaling-mediated inflammation in human vascular endothelial cells. Alcohol Clin Exp Res. 2014 Oct;38(10):2529-40.

[3]. Novel mechanism of cardiac protection by valsartan: synergetic roles of TGF-β1 and HIF-1α in Ang II-mediated fibrosis after myocardial infarction. J Cell Mol Med. 2015 Aug;19(8):1773-82.

[4]. Cardioprotective effect of valsartan in mice with short-term high-salt diet by regulating cardiac aquaporin 1 and angiogenic factor expression. Cardiovasc Pathol. 2015 Jul-Aug;24(4):224-9.

[5]. Valsartan reverses depressive/anxiety-like behavior and induces hippocampal neurogenesis and expression of BDNF protein in unpredictable chronic mild stress mice. Pharmacol Biochem Behav. 2014 Sep;124:5-12.

Therapeutic Uses

Angiotensin II Type 1 Receptor Blocker; Antihypertensive Drug
Diovan is an angiotensin II receptor blocker (ARB) indicated for: treating hypertension and lowering blood pressure. Lowering blood pressure can reduce the risk of fatal and non-fatal cardiovascular events, primarily stroke and myocardial infarction. /Included on US Product Label/
Diovan is an angiotensin II receptor blocker (ARB) indicated for: reducing cardiovascular mortality in patients with clinically stable left ventricular failure or left ventricular dysfunction after myocardial infarction. /Included on US Product Label/
Diovan is an angiotensin II receptor blocker (ARB) indicated for: treating heart failure (NYHA Class II-IV); Diovan significantly reduces hospitalization rates for heart failure. /Included on US Product Label/
For more complete data on the therapeutic uses of valsartan (6 types), please visit the HSDB record page.

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Drug Warnings
/Black Box Warning/ Warning: Fetal toxicity. Discontinue Diovan as soon as pregnancy is discovered. Drugs that act directly on the renin-angiotensin system can cause damage or even death to the developing fetus. Use of drugs acting on the renin-angiotensin system in the second and third trimesters of pregnancy can reduce fetal kidney function and increase fetal and neonatal morbidity and mortality. The resulting oligohydramnios may be associated with fetal lung malformation and skeletal deformities. Potential neonatal adverse reactions include craniosynostosis, anuria, hypotension, renal failure, and death. Diovan should be discontinued as soon as pregnancy is confirmed. These adverse consequences are usually associated with the use of these drugs in the second and third trimesters of pregnancy. Most epidemiological studies investigating fetal malformations following the use of antihypertensive drugs in early pregnancy have not differentiated between drugs affecting the renin-angiotensin system and other antihypertensive drugs. Appropriate management of maternal hypertension during pregnancy is crucial for optimizing maternal and infant outcomes. In rare cases where no suitable alternative therapy is available for a particular patient and drugs affecting the renin-angiotensin system must be used, the pregnant woman should be informed of the potential risks to the fetus. A series of ultrasound examinations should be performed to assess the intraamniotic environment. If oligohydramnios is observed, Diovan should be discontinued unless deemed life-saving for the pregnant woman. Fetal monitoring may be required depending on gestational age. However, patients and physicians should note that oligohydramnios may only occur after irreversible fetal injury. Infants with a history of intrauterine exposure to Diovan should be closely monitored for hypotension, oliguria, and hyperkalemia. Angiotensin II (A-II) is the main effector molecule of the renin-angiotensin system. A-II causes vasoconstriction and sodium and fluid retention by binding to its type 1 (AT1) receptor. In recent years, various AT1 receptor antagonists (collectively known as "sartans") have been marketed for the treatment of hypertension and heart failure. At least 15 case reports describe fetuses of pregnant women taking losartan, candesartan, valsartan, or telmisartan in the mid-to-late stages of pregnancy experiencing various complications, including oligohydramnios, fetal growth restriction, pulmonary hypoplasia, limb contractures, and craniosynostosis. Stillbirth or neonatal death is common in these case reports, and surviving infants may develop kidney damage. Fetal malformations are very similar to those caused by the use of angiotensin-converting enzyme (ACE) inhibitors in pregnant women during the second and third trimesters, possibly due to the fetus's extreme sensitivity to the antihypertensive effects of these drugs. ...
Valsartan is secreted into breast milk in rats. It is unclear whether valsartan is secreted into human breast milk. Due to potential risks to breastfeeding infants, breastfeeding should be discontinued or the drug should be discontinued.
For more complete data on drug warnings for valsartan (21 in total), please visit the HSDB record page.

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Pharmacodynamics
Valsartan inhibits the pressor effect of angiotensin II. Oral administration of 80 mg valsartan inhibits the pressor effect of angiotensin II by approximately 80% at peak, with about 30% inhibition lasting up to 24 hours. Eliminating the negative feedback of angiotensin II can increase plasma renin levels by 2–3 times in hypertensive patients, leading to increased plasma angiotensin II concentrations. After taking valsartan, plasma aldosterone levels decreased only slightly. In multi-dose studies in hypertensive patients, valsartan had no significant effect on total cholesterol, fasting triglycerides, fasting blood glucose, or uric acid. Hypotension: Excessive hypotension was rare (0.1%) in patients with uncomplicated hypertension treated with valsartan alone. Symptomatic hypotension may occur in patients with activated renin-angiotensin system, such as those with volume and/or salt deficiencies treated with high-dose diuretics. This condition should be corrected before taking valsartan or treatment should be initiated under close medical supervision. Caution should be exercised when initiating treatment in patients with heart failure. Patients taking valsartan to treat heart failure typically experience a decrease in blood pressure, but as long as the medication is taken as prescribed, it is usually not necessary to discontinue the medication due to persistent symptomatic hypotension. In controlled trials in patients with heart failure, the incidence of hypotension was 5.5% in the valsartan treatment group and 1.8% in the placebo group. If excessive hypotension occurs, the patient should be placed in a supine position and intravenous saline should be administered if necessary. A transient hypotensive reaction is not a contraindication to continued treatment; treatment can usually be continued smoothly once blood pressure stabilizes. Renal impairment: Renin-angiotensin system inhibitors and diuretics can cause changes in renal function, including acute renal failure. Patients whose renal function is partially dependent on renin-angiotensin system activity (e.g., patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or hypovolemia) may be at higher risk of developing acute renal failure after taking valsartan. Renal function in these patients should be monitored regularly. If a patient experiences a clinically significant decline in renal function after taking valsartan, treatment should be considered for suspension or discontinuation. Hyperkalemia: Some patients with heart failure experience elevated serum potassium. These effects are usually mild and transient and are more likely to occur in patients with pre-existing renal impairment. A dose reduction and/or discontinuation of valsartan may be necessary. Mechanism of action: Valsartan competitively antagonizes AT1R, blocking angiotensin II-mediated vasoconstriction, fibrosis, and inflammation. It can also modulate non-AT1R pathways, such as inhibiting the TLR2/NF-κB signaling pathway and enhancing BDNF expression [2,5]
- Therapeutic applications: It has been approved for the treatment of hypertension, heart failure, and cardiac remodeling after myocardial infarction. Emerging evidence supports its use in the treatment of diabetic nephropathy and neuropsychiatric disorders [1,5]
- Clinical efficacy: In the VALIANT trial (n=14,703), valsartan reduced cardiovascular mortality in patients after myocardial infarction to a similar degree as captopril [10]
- Safety: It is well tolerated with a low incidence of adverse reactions. Common side effects include hypotension (5-8%) and hyperkalemia (2-3%) [1]

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Valsartan (CGP-48933) improves age-related aortic degeneration by blocking AT1R-mediated ERK activation, thereby reducing ASMC apoptosis and MMP-9 expression, and thus protecting aortic elastin and structure [1]
- The mechanism by which valsartan (CGP-48933) inhibits alcohol-induced endothelial inflammation involves inhibiting the TLR2/NF-κB signaling pathway, thereby reducing the production of pro-inflammatory cytokines [2]
- In mice after myocardial infarction, valsartan (CGP-48933) exerts cardioprotective effects through a synergistic mechanism: it downregulates TGF-β1 to reduce collagen synthesis and upregulates HIF-1α to promote angiogenesis, thereby jointly improving left ventricular function [3]
- Valsartan (CGP-48933) protects the heart from high-salt damage by normalizing cardiac AQP1 expression (to reduce water retention) and increasing VEGF (to enhance vascular function) [4]. Valsartan (CGP-48933) reverses UCMS-induced depressive behavior by promoting hippocampal neurogenesis and upregulating BDNF, which may be related to its regulation of the brain's renin-angiotensin system [5].

C24H29N5O3

435.52

435.227

C, 66.19; H, 6.71; N, 16.08; O, 11.02

137862-53-4

Sacubitril/Valsartan;936623-90-4;Valsartan-d9;1089736-73-1;Valsartan-d3;1331908-02-1;Valsartan-d8;1089736-72-0;(Rac)-Valsartan-d9; 137862-53-4; 149690-05-1 (sodium)

60846

White to off-white solid

1.2±0.1 g/cm3

684.9±65.0 °C at 760 mmHg

116-117°C

368.0±34.3 °C

0.0±2.2 mmHg at 25°C

1.587

4.75

2

6

10

32

608

1

O([H])C([C@]([H])(C([H])(C([H])([H])[H])C([H])([H])[H])N(C(C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H])=O)C([H])([H])C1C([H])=C([H])C(C2=C([H])C([H])=C([H])C([H])=C2C2N=NN([H])N=2)=C([H])C=1[H])=O

ACWBQPMHZXGDFX-QFIPXVFZSA-N

InChI=1S/C24H29N5O3/c1-4-5-10-21(30)29(22(16(2)3)24(31)32)15-17-11-13-18(14-12-17)19-8-6-7-9-20(19)23-25-27-28-26-23/h6-9,11-14,16,22H,4-5,10,15H2,1-3H3,(H,31,32)(H,25,26,27,28)/t22-/m0/s1

(S)-3-methyl-2-(N-{[2-(2H-1,2,3,4-tetrazol-5-yl)biphenyl-4-yl]methyl}pentanamido)butanoic acid

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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 (5.74 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), suspension 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 (5.74 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 3: 10 mg/mL (22.96 mM) in 50% PEG300 50% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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