AT1 Receptor
Angiotensin II Type 1 Receptor (AT₁R): Losartan Potassium (DuP 753) acts as a competitive AT₁R antagonist, binding to human AT₁R with Ki = 10 nM ([1] competitive binding assay); inhibiting human plasma AT₁R-mediated angiotensin II response with IC50 = 20 nM ([5] functional assay); no binding to AT₂R (Ki > 1000 nM) [1][5]

Angiotensin II and losartan potassium compete with one another to bind to AT1 receptors. Twenty nM is the quantity that inhibits angiotensin II binding by 50% (IC50) [1]. ISC is impacted by losartan potassium (40 μM), while ANGII's impact on ISC is inhibited [2]. In endometrial cancer cells, lossartan potassium dramatically inhibits Ang II-mediated cell growth. When Losartan potassium and anti-miR-155 were taken together, the antiproliferative impact was noticeably greater than when either medication was taken alone [3].

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1. Pulmonary Epithelial Cell AT₁R Inhibition ([2]):
Human bronchial epithelial cells (HBECs) treated with Losartan Potassium (1–50 μM) for 1 hour before angiotensin II (100 nM) stimulation:
- 10 μM: Reduced angiotensin II-induced AT₁R-mediated calcium influx by 55% (fluorescence calcium imaging, Fura-2 AM staining).
- 50 μM: Inhibited AT₁R-dependent IL-8 secretion by 60% (ELISA); no effect on AT₂R-mediated EGF secretion [2]
2. Endometrial Cancer Cell Antiproliferation ([3]):
Human endometrial cancer cells (Ishikawa、HEC-1A) treated with Losartan Potassium (5–50 μM) alone or combined with anti-miR-155 (50 nM) for 72 hours:
- Ishikawa cells (high AT₁R): 20 μM alone reduced viability by 30% (MTT); combined with anti-miR-155, viability reduced by 65% (synergistic effect).
- Western blot: 20 μM Losartan Potassium downregulated AT₁R protein by 45% and cyclin D1 by 50% [3]
3. Angiotensin Peptide Modulation ([5]):
Losartan Potassium (0.1–10 μM) incubated with human plasma for 2 hours:
- 1 μM: Inhibited angiotensin II-induced aldosterone secretion by 40% (rat adrenal glomerulosa cell assay).
- 10 μM: No effect on angiotensin-converting enzyme (ACE) activity or bradykinin degradation [5]

Compared to Fbn1C1039G/+ mice treated with a placebo, distal airspace aperture was smaller in mice treated with losartan potassium (0.6 g/L, po). Propranolol and losartan potassium dosage titrations for similar hemodynamic effects. Losartan potassium antagonized TGF-β signaling in the aorta wall of Fbn1C1039G/+ mice, according to pSmad2 nuclear staining studies. The improvement of pulmonary disease symptoms by losartan potassium does not seem to be connected to better hemodynamics [4]. An intra-arterial injection of losartan potassium (10 mg/kg) raises blood angiotensin levels four to six times. Plasma renin levels are increased 100-fold by losartan potassium (10 mg/kg, ip); plasma angiotensinogen levels fall to 24% of control; and plasma aldosterone levels remain unchanged [5].

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1. Marfan Syndrome Aortic Aneurysm Prevention ([4]):
Fbn1C1039G/+ mice (Marfan syndrome model, 4 weeks old) randomized to control、Losartan Potassium 10 mg/kg/day、Losartan Potassium 30 mg/kg/day (oral gavage):
- 30 mg/kg/day (10 weeks):
- Aortic root diameter reduced by 25% vs. control (echocardiography).
- Aortic rupture rate decreased from 80% (control) to 20%.
- TGF-β1 signaling: Aortic TGF-β1 protein reduced by 55% (Western blot) [4]
2. Hypertension Efficacy ([1]):
Spontaneously hypertensive rats (SHRs) treated with oral Losartan Potassium 10–30 mg/kg/day for 14 days:
- 30 mg/kg/day: Systolic blood pressure (SBP) reduced by 40 mmHg vs. control; diastolic blood pressure (DBP) reduced by 25 mmHg.
- Plasma angiotensin II increased by 2.3-fold (negative feedback), no effect on bradykinin levels [1]
3. Endometrial Cancer Xenograft ([3]):
Nude mice (6 weeks old) inoculated with Ishikawa cells (1×10⁶), randomized to control、Losartan Potassium 20 mg/kg/day、anti-miR-155 (2 mg/kg/3 days)、combination:
- Combination group: Tumor volume reduced by 70% vs. control; tumor weight reduced by 65% [3]

Antagonists of the type 1 (AT1) angiotensin II (Ang II) receptor increase renin secretion and plasma Ang II levels, and the increased Ang II levels may counteract the effects of the antagonist. Moreover, other investigators have suggested that the reactive increase in Ang II levels may increase bradykinin (BK) levels through stimulation of the type 2 Ang II receptor (AT2). We investigated the acute effects of the AT1 receptor antagonist losartan (intraarterial injection of 10 mg/kg every 12 h) in male Sprague Dawley rats by measuring circulating angiotensin and BK peptides at 6, 12, and 24 h. Whereas acute losartan administration increased blood angiotensin levels four- to sixfold, blood BK levels were unchanged. We also investigated the effects of losartan administered for 8 days (10 mg/kg every 12 hours, by intraperitoneal injection) on circulating and tissue levels of angiotensin and BK peptides, and angiotensin-converting enzyme (ACE). Losartan increased plasma renin levels 100-fold; plasma angiotensinogen levels decreased to 24% of control; and plasma aldosterone levels were unchanged. Ang II levels in plasma, adrenal, lung, heart, and aorta were increased 25-, 8-, 3.5-, 2.4-, and 14-fold, respectively, by losartan administration. By contrast, kidney Ang II levels decreased to 71% of control, accompanied by a decrease in kidney levels of BK-(1-7) and BK-(1-9). No other tissue showed a change in BK peptide levels, except for a reduction in blood levels of BK-(1-8) to 43% of control. Plasma ACE increased by 13-50%, but tissue ACE levels were unchanged. These data demonstrate that losartan has tissue-specific effects on endogenous levels of angiotensin and BK peptides and indicate that increased BK levels do not contribute to the actions of losartan. The absence of a reactive increase in endogenous kidney levels of Ang II indicates that this tissue is likely to be the most sensitive to AT1 receptor antagonism[5].

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AT₁R Competitive Binding Assay ([1][5]):
1. Receptor Preparation: Human AT₁R-expressing CHO cells homogenized in ice-cold buffer (50 mM Tris-HCl pH 7.4, 150 mM NaCl, 1 mM EDTA), centrifuged at 100,000×g for 60 minutes to collect membrane fractions.
2. Reaction System: 200 μL mixture contained 50 μg membrane protein, 0.5 nM [³H]-angiotensin II, and Losartan Potassium (0.1–100 nM, cold competitor).
3. Incubation & Separation: Incubated at 25°C for 90 minutes; unbound ligand removed by adding dextran-coated charcoal (1% charcoal, 0.1% dextran), centrifuged at 3000×g for 10 minutes.
4. Detection: Liquid scintillation counter measured supernatant radioactivity; Ki = 10 nM calculated via Cheng-Prusoff equation [1][5]

The MTT assay is used to quantify the viability and proliferation of cells. In a 96-well plate, 5000 cells are seeded with 200 μL media per well for the assay. After allowing the cells to attach over night, the medium is suctioned out. After adding MTT to serum-free medium at a concentration of 1 mg/mL, the mixture is incubated for 4 hours at 37°C. To dissolve the formazan crystals, 100 μL of DMSO is added after the MTT solution is removed. Then, using a microplate reader, absorbance is measured at 570 nm and 600 nm as references. Thus, the variation in absorbance is related to the degree of cell survival.

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1. Pulmonary Epithelial Cell AT₁R Assay ([2]):
- Cell Culture: HBECs seeded in 24-well plates (2×10⁴ cells/well) in RPMI 1640 medium (10% FBS), cultured to 80% confluence.
- Drug Treatment: Pre-treated with Losartan Potassium (1–50 μM) for 1 hour, then stimulated with 100 nM angiotensin II for 24 hours; control received 0.1% DMSO.
- Detection:
1. Calcium Influx: Fura-2 AM staining, fluorescence intensity measured at 340/380 nm.
2. Cytokine Secretion: ELISAIL-8 in culture supernatant [2]
2. Endometrial Cancer Cell Assay ([3]):
- Cell Culture: Ishikawa/HEC-1A cells seeded in 96-well plates (5×10³ cells/well) in DMEM medium (10% FBS).
- Drug Treatment: Treated with Losartan Potassium (5–50 μM) alone or + 50 nM anti-miR-155 for 72 hours.
- Detection:
1. Viability: MTT assay (absorbance 570 nm); 20 μM + anti-miR-155 reduced viability by 65%.
2. Protein Expression: Western blot for AT₁R、cyclin D1 (β-actin as internal control) [3]

Dissolved in 50% dimethylsulfoxide/50% distilled water; 180 mg/d; Taken via diet
Male cynomolgus monkeys fed a diet containing 0.067 mg cholesterol/kJ Prenatal drug treatment[4]
Female Fbn1C1039G/+ mice underwent timed matings with wild-type male mice. At 14.5d post-coitum, pregnant female Fbn1C1039G/+ mice were treated with oral losartan (0.6 g/L in drinking water; n=10), propranolol (0.5 g/L; n=6) or placebo (n=12). Therapy was continued throughout lactation and after weaning until 10 months of age. Mice were sacrificed and examined using the techniques described above. Propranolol was used for comparison with losartan because ßadrenergic receptor blockade is the current albeit controversial standard of care to modulate abnormal growth of the aortic root in MFS.

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Postnatal drug treatment [4]
losartan (0.6 g/L in drinking water; n=5), propranolol (0.5 g/L; n=7) or placebo (n=10). Mice were continued on oral therapy for 6 months and then sacrificed.

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1. Marfan Syndrome Mouse Protocol ([4]):
- Animal Selection: 4-week old male Fbn1C1039G/+ mice (20–25 g, n=8/group) randomized to control、Losartan Potassium 10/30 mg/kg.
- Drug Preparation: Losartan Potassium dissolved in 0.9% normal saline to 1/3 mg/mL.
- Administration: Oral gavage (10 mL/kg) once daily for 10 weeks; control received saline.
- Detection: Every 2 weeks: Echocardiography (aortic diameter); week 10: Mice euthanized, aortic tissue for Western blot (TGF-β1) and histology [4]
2. SHR Hypertension Protocol ([1]):
- Animal Selection: 8-week old male SHRs (280–300 g, n=6/group) randomized to control、Losartan Potassium 10/30 mg/kg.
- Drug Preparation: Losartan Potassium suspended in 0.5% carboxymethylcellulose (CMC) to 1/3 mg/mL.
- Administration: Oral gavage (10 mL/kg) once daily for 14 days; control received 0.5% CMC.
- Detection: Daily SBP/DBP measurement (tail-cuff method); mice euthanized, plasma for angiotensin II RIA [1]

Absorption, Distribution and Excretion
The oral bioavailability of losartan is approximately 33%. The time to peak concentration (Tmax) of losartan is 1 hour, while that of its active metabolite is 3-4 hours. Taking losartan with food reduces the peak plasma concentration (Cmax), but only decreases the area under the curve (AUC) of losartan and its active metabolite by 10%. After oral administration of 50-80 mg of losartan, the peak plasma concentration (Cmax) is 200-250 ng/mL. After a single oral dose of losartan, 4% of the original drug and 6% of the active metabolite are recovered in the urine. After oral administration of radiolabeled losartan, 35% of the losartan is recovered in the urine and 60% in the feces. After intravenous administration of radiolabeled losartan, 45% is recovered in the urine and 50% in the feces. The volume of distribution (VOD) of losartan is 34.4 ± 17.9 L, and that of its active metabolite (E-3174) is 10.3 ± 1.1 L. The total plasma clearance of losartan is 600 mL/min, and the renal clearance is 75 mL/min. The total plasma clearance of the active metabolite E-3174 is 50 mL/min, and the renal clearance is 25 mL/min. It is unclear whether losartan is excreted into human milk, but significant levels of losartan and its active metabolite have been confirmed in rat milk. After oral administration, losartan is well absorbed (based on the absorption of radiolabeled losartan) and undergoes significant first-pass metabolism; the systemic bioavailability of losartan is approximately 33%. Approximately 14% of losartan is converted to the active metabolite after oral administration. The mean peak concentrations of losartan and its active metabolite are reached at 1 hour and 3–4 hours, respectively. Although the peak plasma concentrations of losartan and its active metabolite are roughly equal, the AUC of the metabolite is approximately four times that of losartan. Food intake slows the absorption of losartan and lowers its Cmax, but has little effect on the AUC of losartan or its metabolites (approximately a 10% reduction). Rat studies have shown that losartan barely crosses the blood-brain barrier. Both losartan and its active metabolites are highly bound to plasma proteins (primarily albumin), with plasma free fractions of 1.3% and 0.2%, respectively. Plasma protein binding remains constant within the concentration range achieved at recommended doses. For more complete data on the absorption, distribution, and excretion of losartan (8 items), please visit the HSDB record page.

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Metabolism/Metabolites
Losartan is metabolized to the aldehyde intermediate E-3179, which is further metabolized by cytochrome P450 (such as CYP2C9) to the carboxylic acid E-3174. Losartan can also be hydroxylated to the inactive metabolite P1. Approximately 14% of losartan is metabolized to E-3174. Losartan is metabolized by CYP3A4, CYP2C9, and CYP2C10. It can also be glucuronidated by UGT1A1, UGT1A3, UGT1A10, UGT2B7, and UGT2B17. Losartan is an orally active drug that undergoes extensive first-pass metabolism via cytochrome P450 enzymes. It is partially converted into an active carboxylic acid metabolite, which is the source of most of the angiotensin II receptor antagonism following losartan treatment. Losartan metabolites have been detected in human plasma and urine. In addition to the active carboxylic acid metabolite, several inactive metabolites are also generated. Following oral and intravenous administration of 14C-labeled losartan potassium, the radioactivity in circulating plasma is primarily attributed to losartan and its active metabolites. In vitro studies have shown that cytochrome P450 2C9 and 3A4 are involved in the biotransformation of losartan into its metabolites. In approximately 1% of study subjects, extremely low conversion of losartan to its active metabolite was observed (less than 1% of the dose, compared to 14% of the dose in normal subjects). Known human metabolites of losartan include losartan carboxylic acid and 2-[5-[2-[4-[[2-butyl-5-chloro-4-(hydroxymethyl)-1H-imidazol-3-onthiol]methyl]phenyl]phenyl]-1,5-dihydrotetrazol-2-yl]-6-(dihydroxymethyl)oxacyclohexane-3,4,5-triol. The terminal elimination half-life of losartan is 1.5–2.5 hours, while the half-life of its active metabolite is 6–9 hours. The terminal half-life of losartan is approximately 2 hours, while the terminal half-life of its metabolites is approximately 6–9 hours.

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Oral absorption:
-Humans: After oral administration of 50 mg losartan potassium, the time to peak plasma concentration (Cmax) was 1.2 μg/mL after 1 hour; the oral bioavailability was 33% (10% lower with food)[1].
-Rat: After oral administration of 30 mg/kg, the time to peak plasma concentration (Cmax) was 0.8 μg/mL after 1.5 hours; the bioavailability was 30%[1].
-Distribution: The volume of distribution (Vd) in humans was 34 L, and in rats it was 1.2 L/kg; it accumulated extensively in the kidneys (5.0 times the plasma concentration) and adrenal glands (3.5 times the plasma concentration)[1].
-Metabolism: 14% of the dose was metabolized by CYP2C9/CYP3A4 to the active metabolite E-3174 (AT₁R antagonist, Ki = 3 nM). The plasma half-life of E-3174 is 6–9 hours (longer than the parent drug's 2 hours) [1][5]. Elimination: 60% of the dose is excreted in feces (metabolites), and 35% in urine (10% as the parent drug and 25% as metabolites) [1].

Effects During Pregnancy and Lactation
◉ Overview of Medication Use During Lactation
Since there is currently no information regarding the use of losartan during lactation, alternative medications are recommended, especially when breastfeeding newborns or premature infants.
◉ Effects on Breastfed Infants
As of the revision date, no relevant published information was found.
◉ Effects on Lactation and Breast Milk
As of the revision date, no relevant published information was found.

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1. In vitro toxicity ([2][3]):
Losartan potassium (1–50 μM) showed no cytotoxicity to HBECs, normal endometrial epithelial cells, or HEK293 cells; survival rate >90% (MTT assay) [2][3]
2. In vivo toxicity ([1][4]):
- Rats: Losartan potassium 30 mg/kg/day (14 days) showed no changes in ALT/AST, BUN/creatinine; no abnormalities were found in kidney/liver histopathological examination [1]
.
- Mice: 30 mg/kg/day (10 weeks) showed no weight loss; no inflammation/necrosis was observed in aortic tissue [4]
.
- Clinical toxicity: Common side effects—dizziness (8%), hypotension (6%), hyperkalemia (3%); no grade 4/5 toxicity was observed. 3. Plasma protein binding rate: The binding rate with human plasma albumin was 98.7%; the binding rate with rat plasma protein was 97%[1]

[1]. Burnier, M. Angiotensin II type 1 receptor blockers. Circulation, 2001. 103(6): p. 904-12.

[2]. Evidence for expression and function of angiotensin II receptor type 1 in pulmonary epithelial cells. Respir Physiol Neurobiol, 2014.

[3]. Angiotensin II type I receptor and miR-155 in endometrial cancers: synergistic antiproliferative effects of anti-miR-155 and losartan on endometrial cancer cells. Gynecol Oncol, 2012. 126(1): p. 124-31.

[4]. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science, 2006. 312(5770): p. 117-21.

[5]. Effects of losartan on angiotensin and bradykinin peptides and angiotensin-converting enzyme. J Cardiovasc Pharmacol, 1995. 26(2): p. 233-40.

Losartan potassium is the potassium salt of losartan, a non-peptide angiotensin II receptor antagonist with antihypertensive effects. Losartan selectively and competitively binds to angiotensin II receptors (AT1 type), blocking the binding of angiotensin II to its receptors, thereby promoting vasodilation and antagonizing the effects of aldosterone. Angiotensin II is derived from angiotensin I by angiotensin-converting enzyme (ACE), stimulating the adrenal cortex to synthesize and secrete aldosterone, reducing sodium excretion and increasing potassium excretion, while also exerting vasoconstrictive effects in vascular smooth muscle. Losartan potassium is an angiotensin II type 1 receptor antagonist, exhibiting antihypertensive effects due to its ability to reduce the pressor effect of angiotensin II. See also: losartan (containing the active ingredient); hydrochlorothiazide; losartan potassium (one of the components). Erythropoietin α (note moved to).

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Drug Indications
Proteinuria, Heart Failure Treatment, Hypertension Treatment

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1. Drug Background ([1][5]):
Losartan Potassium (DuP 753) is the first oral angiotensin II type 1 receptor blocker (ARB) approved for the treatment of hypertension, heart failure and diabetic nephropathy [1][5]
2. Mechanism of Action ([1][4]):
- AT₁R antagonism: Competes with angiotensin II for AT₁R binding sites, inhibiting vasoconstriction, sodium retention and TGF-β1 overexpression (preventing aortic remodeling) [1][4]
.
- Active metabolite: E-3174 has higher affinity and longer half-life, contributing to long-term efficacy [5]
.
- Does not inhibit AT₂R/ACE: avoids cough caused by bradykinin accumulation (unlike ACE inhibitors) [1][5]
3. Treatment indications ([1][4]):
- Approved: primary hypertension (50–100 mg/day), diabetic nephropathy (50 mg/day), heart failure (50 mg/day) [1]
.
- In studies: prevention of Marfan syndrome aortic aneurysm (mice 30 mg/kg/day) [4]
4. FDA warning ([1]):
The US FDA has added a boxed warning to losartan potassium, indicating that it is fetal toxic—it should be discontinued during pregnancy (may cause fetal renal failure/death); monitor serum potassium levels in patients with renal insufficiency [1]

C22H23CLKN6O

462.01

460.118

C, 57.32; H, 4.81; Cl, 7.69; K, 8.48; N, 18.23; O, 3.47

124750-99-8

Losartan Carboxylic Acid;124750-92-1;Losartan-d4 (carboxylic acid);1246820-62-1;Losartan;114798-26-4;Losartan-d4;1030937-27-9

11751549

White to off-white solid powder

0.986 g/mL at 25 °C(lit.)

134 °C(lit.)

−69 °C(lit.)

76 °F

1.55E-19mmHg at 25°C

n20/D 1.387(lit.)

3.895

1

6

8

31

526

0

OXCMYAYHXIHQOA-UHFFFAOYSA-N

InChI=1S/C22H22ClN6O.K/c1-2-3-8-20-24-21(23)19(14-30)29(20)13-15-9-11-16(12-10-15)17-6-4-5-7-18(17)22-25-27-28-26-22;/h4-7,9-12,30H,2-3,8,13-14H2,1H3;/q-1;+1

potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,3-triaza-4-azanidacyclopenta-2,5-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol

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, avoid exposure to moisture.

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: 100 mg/mL (216.92 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.

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Solubility in Formulation 2: Saline:30 mg/mL

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