Angiotensin II receptor

[125I]AII binding to human liver membranes (IC50 of 1.7 nM) and rat mesenteric artery membranes (IC50 of 1.5 nM) is inhibited by eprosartan (SKF-108566J). Eprosartan inhibited the concentration-dependent increases in intracellular Ca2+ levels generated by AII in rabbit aortic smooth muscle cells[1].

Eprosartan (0.01-0.3 mg/kg) administered intravenously (IV) in conscious normotensive rats caused dose-dependent parallel changes in the AII pressor dose-response curve. When conscious normotensive rats were given Eprosartan (3-10 mg/kg) intraduodenally or intragastrically, the pressor response to AII (250 ng/kg, iv) was inhibited in a dose-dependent manner. Significant suppression of the pressor response to AII was seen for three hours at 10 mg/kg, id[1].

---

Eprosartan (EPRO), an angiotensin receptor type-1 (AT-1) blocker, exhibited neuroprotective activities in ischemic stroke resulting from focal cerebral ischemia in rats. The current study aimed to clarify the neuroprotective role of EPRO in middle carotid artery occlusion (MCAO)-induced ischemic stroke in rats. Fifty-six male Wistar rats were divided into four groups (n = 14 per group): sham-operated group, sham receiving EPRO (60 mg/kg/day, po) group, ischemia-reperfusion (IR) group, and IR receiving EPRO (60 mg/kg/day, po) group. MCAO led to a remarkable impairment in motor function together with stimulation of inflammatory and apoptotic pathways in the hippocampus of rats. After MCAO, the AT1 receptor in the brain was stimulated, resulting in activation of Janus kinase 2/signal transducers and activators of transcription 3 signaling generating more neuroinflammatory milieu and destructive actions on the hippocampus. Augmentation of caspase-3 level by MCAO enhanced neuronal apoptosis synchronized with neurodegenerative effects of oxidative stress biomarkers. Pretreatment with EPRO opposed motor impairment and decreased oxidative and apoptotic mediators in the hippocampus of rats. The anti-inflammatory activity of EPRO was revealed by downregulation of nuclear factor-kappa B and tumor necrosis factor-β levels and (C-X-C motif) ligand 1 messenger RNA (mRNA) expression. Moreover, the study confirmed the role of EPRO against a unique pathway of hypoxia-inducible factor-1α and its subsequent inflammatory mediators. Furthermore, upregulation of caveolin-1 mRNA level was also observed along with decreased oxidative stress marker levels and brain edema. Therefore, EPRO showed neuroprotective effects in MCAO-induced cerebral ischemia in rats via attenuation of oxidative, apoptotic, and inflammatory pathways[2].

In rat and human adrenal cortical membranes, SK&F 108566 displaced specifically bound [125I]AII with IC50 of 9.2 and 3.9 nM, respectively. SK&F 108566 also inhibited [125I]AII binding to human liver membranes (IC50 = 1.7 nM) and to rat mesenteric artery membranes (IC50 = 1.5 nM)[1].

In rabbit aortic smooth muscle cells, SK&F 108566 caused a concentration-dependent inhibition of AII-induced increases in intracellular Ca++ levels. In rabbit aortic rings, SK&F 108566 produced parallel rightward shifts in the AII concentration-response curve without affecting the maximal contractile response. Schild analysis of the data yielded a KB value of 0.26 nM and a slope not different from 1, indicative of competition antagonism. SK&F 108566 had no effect on the contractile responses to KCl, norepinephrine or endothelin in rabbit aorta[1].

In conscious normotensive rats, i.v. administration of SK&F 108566 (0.01-0.3 mg/kg) produced dose-dependent parallel shifts in the AII pressor dose-response curve. Administration of SK&F 108566 (3-10 mg/kg) intraduodenally or intragastrically to conscious normotensive rats resulted in a dose-dependent inhibition of the pressor response to AII (250 ng/kg, i.v.). At 10 mg/kg, i.d., significant inhibition of the pressor response to AII was observed for 3 hr. In this same rat model, SK&F 108566 had no effect on base-line pressure or on the pressor response to norepinephrine or vasopressin. The data demonstrate that SK&F 108566 is a potent, highly selective, competitive nonpeptide AII antagonist.

---

3 mg/kg-10 mg/kg, administered by duodenal or gastric catheter

Rats

Absorption, Distribution and Excretion
Absolute bioavailability following a single 300 mg oral dose of eprosartan is approximately 13%. Administering eprosartan with food delays absorption.
Eprosartan is excreted in animal milk; it is not known whether eprosartan is excreted in human milk.
Plasma protein binding of eprosartan is high (approximately 98%) and constant over the concentration range achieved with therapeutic doses. The pooled population pharmacokinetic analysis from two Phase 3 trials of 299 men and 172 women with mild to moderate hypertension (aged 20 to 93 years) showed that eprosartan exhibited a population mean oral clearance (CL/F) for an average 60-year-old patient of 48.5 L/hr. The population mean steady-state volume of distribution (Vss/F) was 308 L. Eprosartan pharmacokinetics were not influenced by weight, race, gender or severity of hypertension at baseline. Oral clearance was shown to be a linear function of age with CL/F decreasing 0.62 L/hr for every year increase.
Eprosartan is eliminated by biliary and renal excretion, primarily as unchanged compound. Less than 2% of an oral dose is excreted in the urine as a glucuronide. There are no active metabolites following oral and intravenous dosing with (14)C eprosartan in human subjects. Eprosartan was the only drug-related compound found in the plasma and feces. Following intravenous (14)C eprosartan, about 61% of the material is recovered in the feces and about 37% in the urine. Following an oral dose of (14)C eprosartan, about 90% is recovered in the feces and about 7% in the urine.
Absolute bioavailability following a single 300 mg oral dose of eprosartan is approximately 13%. Eprosartan plasma concentrations peak at 1 to 2 hours after an oral dose in the fasted state. Administering eprosartan with food delays absorption, and causes variable changes (<25%) in Cmax and AUC values which do not appear clinically important. Plasma concentrations of eprosartan increase in a slightly less than dose-proportional manner over the 100 mg to 800 mg dose range. The mean terminal elimination half-life of eprosartan following multiple oral doses of 600 mg was approximately 20 hours. Eprosartan does not significantly accumulate with chronic use.
For more Absorption, Distribution and Excretion (Complete) data for EPROSARTAN (6 total), please visit the HSDB record page.

---

Metabolism / Metabolites
Eprosartan is not metabolized by the cytochrome P450 system. It is mainly eliminated as unchanged drug. Less than 2% of an oral dose is excreted in the urine as a glucuronide.
Following an oral dose of (14)C eprosartan, about 90% is recovered in the feces and about 7% in the urine. Approximately 20% of the radioactivity excreted in the urine was an acyl glucuronide of eprosartan with the remaining 80% being unchanged eprosartan.

---

Biological Half-Life
The terminal elimination half-life of eprosartan following oral administration is typically 5 to 9 hours.
... The mean terminal elimination half-life of eprosartan following multiple oral doses of 600 mg was approximately 20 hours. ...
After oral administration of eprosartan to healthy volunteers ... the drug's terminal elimination half-life is typically 5-9 hours after oral administration. ...

Hepatotoxicity
Eprosartan has been associated with a low rate of serum aminotransferase elevations (
Likelihood score: E* (Unproved but suspected rare cause of clinically apparent liver injury).

---

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

---

Protein Binding
Plasma protein binding of eprosartan is high (approximately 98%) and constant over the concentration range achieved with therapeutic doses.

[1]. Pharmacological characterization of the nonpeptide angiotensin II receptor antagonist, SK&F 108566. J Pharmacol Exp Ther. 1992 Jan;260(1):175-81.

Eprosartan methanesulfonate is a methanesulfonate salt. It has a role as an antihypertensive agent. It contains an eprosartan.
Eprosartan Mesylate is the mesylate salt form of eprosartan, a non-biphenyl, non-tetrazole, nonpeptide angiotensin II antagonist with antihypertensive activity. Eprosartan mesylate antagonizes angiotensin II type I receptors in tissues such as vascular smooth muscle and the adrenal gland. This prevents angiotensin II-induced vasoconstriction and prevents angiotensin II-mediated stimulation of aldosterone secretion by the adrenal cortex, which decreases the excretion of sodium and water and increases the excretion of potassium.
See also: Eprosartan mesylate; hydrochlorothiazide (component of).

C23H24N2O4S.CH4O3S

520.62

520.133

C, 55.37; H, 5.42; N, 5.38; O, 21.51; S, 12.32

144143-96-4

Eprosartan;133040-01-4

5282474

White to off-white solid powder

1.26 g/cm3

660.6ºC

248 °C

353.3ºC

2.37E-18mmHg at 25°C

5.329

3

9

10

35

711

0

CCCCC1=NC=C(N1CC2=CC=C(C=C2)C(=O)O)/C=C(\CC3=CC=CS3)/C(=O)O.CS(=O)(=O)O

DJSLTDBPKHORNY-XMMWENQYSA-N

InChI=1S/C23H24N2O4S.CH4O3S/c1-2-3-6-21-24-14-19(12-18(23(28)29)13-20-5-4-11-30-20)25(21)15-16-7-9-17(10-8-16)22(26)27;1-5(2,3)4/h4-5,7-12,14H,2-3,6,13,15H2,1H3,(H,26,27)(H,28,29);1H3,(H,2,3,4)/b18-12+;

4-[[2-butyl-5-[(E)-2-carboxy-3-thiophen-2-ylprop-1-enyl]imidazol-1-yl]methyl]benzoic acid;methanesulfonic acid

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: ≥ 2.08 mg/mL (4.00 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 20.8 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: ≥ 2.08 mg/mL (4.00 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 20.8 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.

---

View More

Solubility in Formulation 3: ≥ 2.08 mg/mL (4.00 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 20.8 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.)