AT1 Receptor

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].

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].

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].

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.

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.

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

Absorption, Distribution and Excretion
Losartan is approximately 33% orally bioavailable. Losartan has a Tmax of 1 hour and the active metabolite has a Tmax of 3-4 hours. Taking losartan with food decreases the Cmax but does only results in a 10% decrease in the AUC of losartan and its active metabolite. A 50-80mg oral dose of losartan leads to a Cmax of 200-250ng/mL.
A single oral dose of losartan leads to 4% recovery in the urine as unchanged losartan, 6% in the urine as the active metabolite. Oral radiolabelled losartan is 35% recovered in urine and 60% in feces. Intravenous radiolabelled losartan is 45% recovered in urine and 50% in feces.
The volume of distribution of losartan is 34.4±17.9L and 10.3±1.1L for the active metabolite (E-3174).
Losartan has a total plasma clearance of 600mL/min and a renal clearance of 75mL/min. E-3174, the active metabolite, has a total plasma clearance of 50mL/min and a renal clearance of 25mL/min.
It is not known whether losartan is excreted in human milk, but significant levels of losartan and its active metabolite were shown to be present in rat milk.
Following oral administration, losartan is well absorbed (based on absorption of radiolabeled losartan) and undergoes substantial first-pass metabolism; the systemic bioavailability of losartan is approximately 33%. About 14% of an orally-administered dose of losartan is converted to the active metabolite. Mean peak concentrations of losartan and its active metabolite are reached in 1 hour and in 3-4 hours, respectively. While maximum plasma concentrations of losartan and its active metabolite are approximately equal, the AUC of the metabolite is about 4 times as great as that of losartan. A meal slows absorption of losartan and decreases its Cmax but has only minor effects on losartan AUC or on the AUC of the metabolite (about 10% decreased).
Studies in rats indicate that losartan crosses the blood-brain barrier poorly, if at all.
Both losartan and its active metabolite are highly bound to plasma proteins, primarily albumin, with plasma free fractions of 1.3% and 0.2%, respectively. Plasma protein binding is constant over the concentration range achieved with recommended doses.
For more Absorption, Distribution and Excretion (Complete) data for Losartan (8 total), please visit the HSDB record page.

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Metabolism / Metabolites
Losartan is metabolized to an aldehyde intermediate, E-3179, which is further metabolized to a carboxylic acid, E-3174, by cytochrome P450s like CYP2C9. Losartan can also be hydroxylated to an inactive metabolite, P1. Approximately 14% of losartan is metabolized to E-3174. Losartan can be metabolized by CYP3A4, CYP2C9, and CYP2C10. Losartan can also be glucuronidated by UGT1A1, UGT1A3, UGT1A10, UGT2B7, and UGT 2B17.
Losartan is an orally active agent that undergoes substantial first-pass metabolism by cytochrome P450 enzymes. It is converted, in part, to an active carboxylic acid metabolite that is responsible for most of the angiotensin II receptor antagonism that follows losartan treatment. Losartan metabolites have been identified in human plasma and urine. In addition to the active carboxylic acid metabolite, several inactive metabolites are formed. Following oral and intravenous administration of (14)C-labeled losartan potassium, circulating plasma radioactivity is primarily attributed to losartan and its active metabolite. In vitro studies indicate that cytochrome P450 2C9 and 3A4 are involved in the biotransformation of losartan to its metabolites. Minimal conversion of losartan to the active metabolite (less than 1% of the dose compared to 14% of the dose in normal subjects) was seen in about one percent of individuals studied.
Losartan has known human metabolites that include Losartan carboxylic acid and 2-[5-[2-[4-[[2-butyl-5-chloro-4-(hydroxymethyl)-1H-imidazol-3-ium-3-yl]methyl]phenyl]phenyl]-1,5-dihydrotetrazol-2-yl]-6-(dihydroxymethyl)oxane-3,4,5-triol.

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Biological Half-Life
The terminal elimination half life of losartan is 1.5-2.5 hours while the active metabolite has a half life of 6-9 hours.
The terminal half-life of losartan is about 2 hours and of the metabolite is about 6-9 hours.

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Because no information is available on the use of losartan during breastfeeding, 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.

[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 activity. Losartan selectively and competitively binds to the angiotensin II receptor (type AT1) and blocks the binding of angiotensin II to the receptor, thus promoting vasodilatation and counteracting the effects of aldosterone. Converted from angiotensin I by angiotensin-converting enzyme (ACE), angiotensin II stimulates the adrenal cortex to synthesize and secrete aldosterone, decreasing sodium excretion and increasing potassium excretion, and acts as a vasoconstrictor in vascular smooth muscle.
An antagonist of ANGIOTENSIN TYPE 1 RECEPTOR with antihypertensive activity due to the reduced pressor effect of ANGIOTENSIN II.
See also: Losartan (has active moiety); Hydrochlorothiazide; Losartan Potassium (component of); Epoetin Alfa (annotation moved to).

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Drug Indication
Proteinuria, Treatment of heart failure, Treatment of hypertension

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.)