Angiotensin II receptor

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

Eprosartan (0.01-0.3 mg/kg) administered intravenously caused dose-dependent parallel shifts in the AII pressor dose-response curve in conscious normotensive rats. When conscious normotensive rats were given Eprosartan (3-10 mg/kg) intraduodenally or intragastrically, the pressor response to AII (250 ng/kg, i.v.) was inhibited in a dose-dependent manner. For three hours, a notable suppression of the pressor response to AII was noted at 10 mg/kg, i.d.[1].

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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.

Absorption, Distribution and Excretion
The absolute bioavailability of eprosartan after a single oral dose of 300 mg is approximately 13%. Co-administration with food delays the absorption of eprosartan. Eprosartan is excreted into animal milk; it is unknown whether it is excreted into human milk. Eprosartan has a high plasma protein binding rate (approximately 98%), which remains stable within the therapeutic dose range. A pooled population pharmacokinetic analysis of two phase 3 clinical trials included 299 men and 172 women with mild to moderate hypertension (aged 20 to 93 years). Results showed that for patients with a mean age of 60 years, the population mean oral clearance (CL/F) of eprosartan was 48.5 L/hr. The population mean steady-state volume of distribution (Vss/F) was 308 L. The pharmacokinetics of eprosartan were not affected by weight, race, sex, or baseline hypertension severity. Oral clearance is linearly related to age, decreasing by 0.62 L/hr for every year of age increase in CL/F. Eprosartan is primarily excreted unchanged via bile and kidneys. Less than 2% of the oral dose is excreted in the urine as glucuronide. In human subjects, no active metabolites were detected after oral and intravenous administration of (14)C-labeled eprosartan. Eprosartan was the only drug-related compound detected in plasma and feces. After intravenous administration of (14)C-labeled eprosartan, approximately 61% of the drug was recovered in feces and approximately 37% in urine. After oral administration of 14C-labeled eprosartan, approximately 90% was excreted in feces and approximately 7% in urine. The absolute bioavailability of a single oral dose of 300 mg eprosartan is approximately 13%. After oral administration of eprosartan on an empty stomach, peak plasma concentrations are reached within 1 to 2 hours. Taking it with food delays absorption and causes varying degrees of change (<25%) in C_max and AUC values, which appear to be clinically insignificant. Within the dose range of 100 mg to 800 mg, the increase in plasma concentration of eprosartan is slightly less than dose-proportional. Following multiple oral doses of 600 mg eprosartan, the mean terminal elimination half-life is approximately 20 hours. Long-term use of eprosartan does not result in significant accumulation. For more complete data on the absorption, distribution, and excretion of eprosartan (6 types), please visit the HSDB record page. Metabolites/Metabolites: Eprosartan is not metabolized by the cytochrome P450 system. It is primarily excreted unchanged. Of the oral dose, less than 2% is excreted in the urine as glucuronide. Following oral administration of 14C-labeled eprosartan, approximately 90% is excreted in feces and approximately 7% in urine. Approximately 20% of the radioactive material excreted in urine is acyl glucuronide of eprosartan, and the remaining 80% is unmetabolized eprosartan.
Biological Half-Life
The terminal elimination half-life after oral administration of eprosartan is typically 5 to 9 hours. …After multiple oral administrations of 600 mg eprosartan, the average terminal elimination half-life is approximately 20 hours. … In healthy volunteers, after oral administration of eprosartan… the terminal elimination half-life of this drug is typically 5–9 hours after oral administration. …

Toxicity Summary
Identification and Use: Eprosartan is a white to off-white crystalline powder formulated as oral tablets. Eprosartan is an angiotensin II type 1 (AT1) receptor antagonist. It can be used alone or in combination with other classes of antihypertensive drugs to treat hypertension. Human Exposure and Toxicity: Eprosartan is contraindicated during pregnancy. While use in early pregnancy does not indicate a significant risk of teratogenicity, 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 may lead to fetal limb contractures, craniofacial malformations, and pulmonary dysplasia. Neonates exposed to eprosartan in utero may develop severe anuria and hypotension unresponsive to vasopressors and volume expansion therapy. In vitro human peripheral blood lymphocyte assays showed that eprosartan had chromosome breakage-inducing effects under metabolic activation conditions but not under metabolic deactivation conditions. In the same assay, eprosartan induced polyploidy under metabolic activation conditions but not under metabolic deactivation conditions. Animal studies: In diet-restricted rats and free-feeding mice, eprosartan did not show carcinogenicity after continuous administration at doses of 600 mg/kg/day and 2000 mg/kg/day, respectively, for up to 2 years. Furthermore, the reproductive capacity of male and female rats was not affected by eprosartan administration. When pregnant rats were given oral doses of up to 1000 mg/kg/day, no adverse effects on intrauterine or postnatal development and maturation of offspring were observed. However, in pregnant rabbits, oral administration of eprosartan has been shown to produce maternal and fetal toxicity (including maternal and fetal death, reduced maternal weight and food intake, embryo resorption, abortion, and pup death). Eprosartan is not mutagenic in vitro against bacteria or mammalian cells (mouse lymphoma assay). In vivo (mouse micronucleus assay) eprosartan also did not cause chromosomal structural damage.

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Hepatotoxicity
Eprosartan is associated with a low incidence of elevated serum transaminases (
Probability score: E (unproven, but suspected as a rare cause of clinically significant liver injury)).

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Effects during pregnancy and lactation
◉ Overview of use during lactation
Because there is no information on the use of eprosartan during lactation, other medications may be preferred, especially for breastfed newborns or preterm infants.
◉ Effects on breastfed infants
No published information found as of the revision date.
◉ Effects on lactation and breast milk
No published information found as of the revision date. Plasma protein binding: Eprosartan maintains a high and stable plasma protein binding rate (approximately 98%) within the therapeutic dose range. Drug interactions: Concomitant use of lithium with angiotensin II receptor agonists has been reported to lead to elevated serum lithium concentrations and lithium toxicity. Serum lithium levels should be monitored during concomitant use. Alisartan is contraindicated in diabetic patients with concomitant use with tevistan. Concomitant use of alisartan with tevistan should be avoided in patients with renal insufficiency (glomerular filtration rate <60 mL/min). Dual blockade of the renin-angiotensin system (RAS) with angiotensin receptor blockers, ACE inhibitors, or alisartan compared to monotherapy increases the risk of hypotension, hyperkalemia, and altered renal function (including acute renal failure). Most patients receiving combination therapy with two RAS inhibitors do not experience additional benefit compared to monotherapy. In general, concomitant use of RAS inhibitors should be avoided. Close monitoring is necessary. Patients taking teveten and other medications that affect the renin-angiotensin system (RAS) may experience impaired blood pressure, renal function, and electrolyte levels. Potential drug interactions (reduced antihypertensive effect) may exist when angiotensin II receptor antagonists are used in combination with nonsteroidal anti-inflammatory drugs (NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors). Renal function may worsen in elderly patients, patients with hypovolemia (including those receiving concurrent diuretics), or patients with impaired renal function; patients receiving eprosartan in combination with NSAIDs (including selective COX-2 inhibitors) should have their renal function monitored regularly. For more complete (7 items) data on drug interactions with eprosartan, please visit the HSDB record page.

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

[2]. Eprosartan: A closer insight into its neuroprotective activity in rats with focal cerebral ischemia-reperfusion injury. J Biochem Mol Toxicol. 2021 Jul;35(7):e22796.

Therapeutic Uses
Angiotensin II type 2 receptor blocker; antihypertensive drug. Tevitan is indicated for the treatment of hypertension. It can be used alone or in combination with other antihypertensive drugs, such as diuretics and calcium channel blockers. /Included on US product label/ Angiotensin II receptor antagonists (including eprosartan) and ACE inhibitors have both been shown to slow the progression of kidney disease in hypertensive patients with diabetes and microalbuminuria or overt nephropathy, and one of these classes of drugs is recommended for such patients. /Not included on US product label/ Angiotensin II receptor antagonists (including eprosartan) have been used to treat congestive heart failure. While angiotensin II receptor antagonists appear to have similar hemodynamic effects to ACE inhibitors, some experts note that in the absence of data demonstrating comparable long-term cardiovascular and/or renal benefits, angiotensin II receptor antagonists should primarily be reserved for patients for whom ACE inhibitors are indicated but cannot be tolerated (e.g., due to intractable cough or angioedema). /Not included on US product label/

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Drug Warning
/Black Box Warning/ Warning: Fetal toxicity. Teveten should be discontinued as soon as pregnancy is confirmed. Drugs that act directly on the renin-angiotensin system can cause damage or even death to the developing fetus.
Use of drugs that act on the renin-angiotensin system in the second or third trimester can reduce fetal kidney function and increase fetal and neonatal morbidity and mortality. Oligohydramnios can lead to fetal lung hypoplasia and skeletal malformations. Potential neonatal adverse reactions include craniosynostosis, anuria, hypotension, renal failure, and death. Teveten should be discontinued as soon as pregnancy is confirmed. These adverse reactions are often associated with use of such drugs in the second or third trimester. Most epidemiological studies investigating fetal abnormalities following the use of antihypertensive drugs in early pregnancy have not differentiated between drugs that affect 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 other suitable alternative therapy is available for a particular patient, the pregnant woman should be informed of the potential risks of the drug to the fetus. Perform a series of ultrasound examinations to assess the amniotic cavity environment. If oligohydramnios is observed, Teveten should be discontinued unless deemed life-saving for the pregnant woman. Fetal examinations may be required depending on gestational age. However, patients and physicians should note that oligohydramnios may only occur after irreversible damage to the fetus. Newborns with a history of intrauterine exposure to Teveten: If oliguria or hypotension occurs, focus should be placed on maintaining blood pressure and renal perfusion. Exchange transfusion or dialysis may be necessary to reverse hypotension and/or replace impaired renal function. FDA Pregnancy Risk Category: D/Clear evidence of risk. Fetal risk has been confirmed in human studies, investigational data, or post-marketing data. Nevertheless, the potential benefits of using this drug may outweigh the potential risks. For example, this drug may be appropriate in life-threatening situations or when the patient has a serious illness for which other safer medications are unavailable or ineffective. / For more complete (17) drug warnings for Eprosartan, please visit the HSDB record page.

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Pharmacodynamics
Angiotensin II is the main vasopressor of the renin-angiotensin system, produced from angiotensin I under the catalysis of angiotensin-converting enzyme (kininase II). It is responsible for vasoconstriction, stimulating aldosterone synthesis and release, cardiac excitation, and renal sodium reabsorption. Eprosartan selectively blocks the binding of angiotensin II to AT1 receptors, resulting in a variety of effects, including vasodilation, reduced vasopressin secretion, and reduced aldosterone production and secretion. The result is a decrease in blood pressure.

C23H24N2O4S

424.51

424.145

C, 65.07; H, 5.70; N, 6.60; O, 15.08; S, 7.55

133040-01-4

Eprosartan mesylate; 144143-96-4; Eprosartan-d3; 1185243-70-2

5281037

White to off-white solid powder

1.3±0.1 g/cm3

660.6±55.0 °C at 760 mmHg

250-253ºC

353.3±31.5 °C

0.0±2.1 mmHg at 25°C

1.628

4.96

2

6

10

30

618

0

O=C(O)C1=CC=C(CN2C(/C=C(C(O)=O)\CC3=CC=CS3)=CN=C2CCCC)C=C1

OROAFUQRIXKEMV-LDADJPATSA-N

InChI=1S/C23H24N2O4S/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/h4-5,7-12,14H,2-3,6,13,15H2,1H3,(H,26,27)(H,28,29)/b18-12+

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

Regulaten; Futuran; Navixen; Teveten; SKF-108566; SKF108566; Teveten; SKF 108566; SK and F 108566

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)

DMSO: ~125 mg/mL (~294.5 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (4.90 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.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (4.90 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.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (4.90 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.

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