Losartan

Competitive and Selective AT1 Receptor Antagonism

This compound functions as a competitive antagonist at the AT1 receptor. drugbank.comtandfonline.com This means that this compound competes with angiotensin II for the same binding site on the receptor. drugbank.comahajournals.org By occupying this site, this compound prevents angiotensin II from binding and activating the receptor. patsnap.comdrugbank.com

Research indicates that this compound exhibits high selectivity for the AT1 receptor compared to the AT2 receptor. drugbank.comnih.gov this compound and its active metabolite demonstrate significantly greater affinity for the AT1 receptor, approximately 1000 times more than for the AT2 receptor. drugbank.com This selectivity is crucial for its therapeutic profile, minimizing potential effects mediated by the AT2 receptor. Studies have shown that this compound selectively antagonizes angiotensin II-induced contraction in vascular tissues without inhibiting contractions induced by other agonists like KCl, norepinephrine, serotonin, or endothelin, further confirming its selective AT1 receptor antagonism. oup.com

Role of the Active Metabolite, EXP3174 (E3174), in Receptor Binding and Efficacy

This compound is a prodrug that undergoes significant first-pass metabolism in the liver, primarily via cytochrome P450 enzymes like CYP2C9 and CYP3A4, to form a more potent active metabolite known as EXP3174 (also referred to as E3174 or this compound carboxylic acid). patsnap.comnih.govnih.govresearchgate.net This metabolite plays a significant role in the pharmacological activity of this compound. mdpi.com

Differentiation from Angiotensin-Converting Enzyme (ACE) Inhibitors Regarding Bradykinin Pathway Modulation

Angiotensin-Converting Enzyme (ACE) inhibitors and Angiotensin II Receptor Blockers (ARBs) like this compound both impact the RAAS but differ in their mechanism regarding the bradykinin pathway. ACE is the enzyme responsible for converting angiotensin I to angiotensin II. patsnap.com ACE also plays a role in the degradation of bradykinin, a potent vasodilator. nih.gov

ACE inhibitors block the activity of ACE, thereby reducing angiotensin II production and preventing the breakdown of bradykinin. nih.gov The accumulation of bradykinin is thought to contribute to some of the effects of ACE inhibitors, including vasodilation and, in some cases, adverse effects like cough and angioedema. nih.gov

In contrast, this compound, as an ARB, directly blocks the AT1 receptor and does not inhibit ACE. patsnap.comnih.gov Therefore, this compound does not interfere with the breakdown of bradykinin by ACE. nih.gov This difference in mechanism explains why ARBs like this compound are associated with a lower incidence of bradykinin-related side effects such as cough, compared to ACE inhibitors. drugbank.comnih.gov Studies have shown that this compound does not alter the vasodilator response to bradykinin in the human forearm, highlighting this distinction. ahajournals.org

Regulation of Vasomotor Tone and Aldosterone Secretion Pathways

Angiotensin II is a potent vasoconstrictor, and its binding to the AT1 receptor in vascular smooth muscle leads to increased vasomotor tone and elevated blood pressure. patsnap.comdrugbank.comnih.gov By blocking the AT1 receptor, this compound prevents this vasoconstrictive effect, leading to relaxation of blood vessels and a reduction in peripheral resistance, which in turn lowers blood pressure. patsnap.comdrugbank.com

Angiotensin II also stimulates the adrenal glands to release aldosterone. patsnap.comdrugbank.comnih.gov Aldosterone is a mineralocorticoid hormone that promotes sodium and water reabsorption in the kidneys, leading to increased blood volume and elevated blood pressure. patsnap.comnih.gov this compound's blockade of the AT1 receptor inhibits the angiotensin II-induced secretion of aldosterone. patsnap.comnih.gov This reduction in aldosterone levels leads to decreased sodium and water retention and increased excretion of sodium and water by the kidneys, further contributing to the blood pressure-lowering effect. patsnap.com this compound also increases the urinary excretion of potassium, chloride, magnesium, uric acid, and calcium. nih.gov

The impact of this compound on vasomotor tone and aldosterone secretion is a cornerstone of its therapeutic utility in conditions like hypertension. patsnap.comdrugbank.com

Modulation of Cellular Hypertrophy and Hyperplasia

Beyond its effects on vasomotor tone and aldosterone, angiotensin II also plays a role in stimulating cellular growth and proliferation, contributing to structural changes in the cardiovascular system, such as vascular and cardiac hypertrophy and hyperplasia. nih.govahajournals.org These changes can contribute to the progression of cardiovascular diseases.

Influence on Neurohormonal Responses

This compound's primary mechanism involves disrupting the renin-angiotensin-aldosterone system (RAAS). By blocking the AT1 receptor, this compound inhibits the negative feedback loop on renin release, leading to compensatory increases in plasma renin activity and angiotensin II concentrations. Despite the elevated levels of angiotensin II, the AT1 receptor blockade by this compound prevents its downstream effects. This blockade also leads to a reduction in aldosterone secretion. Studies in patients with congestive heart failure have shown that this compound administration results in dose-dependent neurohormonal effects, including increased plasma renin activity and angiotensin II levels, alongside significantly lowered aldosterone concentrations. The extent of these neurohormonal changes can vary, and in some populations, such as hypertensive patients with obstructive sleep apnea, the reduction in aldosterone levels following this compound treatment may be less pronounced compared to those without the condition.

Diuretic and Natriuretic Mechanisms Beyond Hemodynamic Changes

While the primary diuretic and natriuretic effects of this compound are often linked to its hemodynamic actions resulting from AT1 receptor blockade (reducing vasoconstriction and thus increasing renal blood flow and pressure, leading to increased filtration and reduced sodium and water reabsorption), there is some evidence suggesting mechanisms that might extend beyond these hemodynamic alterations. Blocking the AT1 receptor directly in the kidney can influence tubular function, affecting sodium and water handling. Angiotensin II, acting via AT1 receptors, promotes sodium reabsorption in various parts of the nephron, including the proximal tubules and collecting ducts. By blocking these receptors, this compound can reduce this pro-reabsorptive effect, leading to increased sodium and water excretion. While some studies in specific animal models have shown no significant changes in urine volume or electrolyte excretion with this compound, others indicate that this compound can reduce the reabsorption of sodium and increase luminal fluid volume by reducing intraluminal angiotensin II. This suggests a more direct tubular effect independent of systemic hemodynamic changes.

AT1 Receptor-Independent Mechanisms

A significant aspect of this compound's anti-inflammatory and anti-aggregatory actions is that they can occur independently of its primary AT1 receptor blockade. This has been speculated partly because these properties are not consistently shared by all other AT1 receptor blockers or by angiotensin-converting enzyme inhibitors. These AT1 receptor-independent effects include the inhibition of monocyte recruitment and signaling pathways crucial for inflammatory processes and potentially cancer metastasis. This compound and its primary metabolite, EXP3174, have been shown to inhibit monocyte recruitment by noncompetitively inhibiting CCL2-induced ERK1/2 activation, independent of AT1 receptor activity.

Interaction with Thromboxane A2/Prostaglandin Endoperoxide H2 (TXA2/PGH2) Receptor

This compound and its active metabolite, EXP3174, can interact with and antagonize the thromboxane A2/prostaglandin H2 (TXA2/PGH2) receptor, also known as the thromboxane receptor (TP receptor). This interaction contributes to this compound's anti-aggregatory effects by blocking the vasoconstriction and platelet aggregation induced by TXA2 and PGH2. Studies have demonstrated that this compound can block platelet aggregation induced by TXA2 analogs and displace ligand binding to the TXA2 receptor, suggesting a dual-receptor antagonist activity alongside its AT1 blockade. This interaction with the TXA2/PGH2 receptor appears to be a molecule-specific effect not shared by all other ARBs.

Cyclooxygenase (COX) Inhibition by Metabolites

The anti-inflammatory properties of this compound are also mediated, in part, by its metabolites, particularly EXP3179 (this compound carboxaldehyde). EXP3179 has been shown to inhibit cyclooxygenase (COX) activity, specifically by abolishing the upregulation of COX-2 mRNA and reducing the COX-dependent generation of prostaglandins, including TXA2 and prostaglandin F2α. This metabolite demonstrates structural homology to known cyclooxygenase inhibitors like indomethacin. While EXP3179 has no AT1 receptor-blocking activity, its ability to inhibit COX-2 contributes significantly to the anti-inflammatory actions observed with this compound. Serum levels of EXP3179 detectable in patients have been associated with reduced platelet aggregation.

Anti-inflammatory and Anti-aggregatory Activities

Interaction with Thromboxane A2/Prostaglandin Endoperoxide H2 (TXA2/PGH2) Receptor

Oral Bioavailability and First-Pass Metabolism

Following oral administration, this compound is well absorbed from the gastrointestinal tract. mims.comfda.govpharmgkb.org However, it undergoes substantial first-pass metabolism in the liver. mims.comfda.govnih.gov This first-pass effect contributes to a relatively low systemic bioavailability, which is reported to be approximately 33%. wikipedia.orgmims.comfda.govnih.govnih.gov The low bioavailability is primarily attributed to this variable first-pass metabolism. pharmgkb.orgmdpi.com Peak plasma concentrations of this compound are typically reached within about 1 hour after oral administration. mims.comfda.govpharmgkb.orgnih.gov

Hepatic Metabolism via Cytochrome P450 (CYP) Enzymes (CYP2C9, CYP3A4, CYP2C10)

This compound is primarily metabolized in the liver by cytochrome P450 (CYP) enzymes. wikipedia.orgmims.comfda.govnih.gov The main isoenzymes involved in the biotransformation of this compound are CYP2C9 and CYP3A4. wikipedia.orgmims.comfda.govdroracle.aipharmgkb.orgnih.govdrugbank.comdrugsporphyria.netresearchgate.net In vitro studies have indicated that CYP2C9 is the dominant isoenzyme responsible for this compound oxidation at physiological concentrations, while CYP3A4 plays a more significant role at higher drug concentrations. pharmgkb.orgdrugsporphyria.net Some sources also mention the involvement of CYP2C10 in this compound metabolism. droracle.aidrugbank.comdrugsporphyria.netresearchgate.net The metabolism of this compound involves oxidation, hydroxylation, and glucuronidation pathways. pharmgkb.orgdrugbank.com

Formation and Contribution of Active Metabolites

A significant portion of an orally administered dose of this compound, approximately 14%, is converted to a pharmacologically active carboxylic acid metabolite, known as EXP3174 (or E-3174). wikipedia.orgfda.govpharmgkb.orgnih.govmdpi.comdrugbank.combrieflands.com This biotransformation from this compound to EXP3174 involves the oxidation of an alcohol to a carboxylic acid, catalyzed by CYP enzymes, with E-3179 as an aldehyde intermediate. pharmgkb.orgdrugbank.combrieflands.comtaltech.ee EXP3174 is a key contributor to the therapeutic effects of this compound, as it is significantly more potent than the parent compound in blocking the AT₁ receptor, with reported potencies ranging from 10 to 40 times greater than this compound. wikipedia.orgfda.govpharmgkb.orgmdpi.comdrugbank.comdrugsporphyria.netbrieflands.comfda.gov The active metabolite is largely responsible for the duration of action of this compound. pharmgkb.org Peak plasma concentrations of EXP3174 are typically reached later than those of this compound, occurring around 3-4 hours after oral administration. wikipedia.orgmims.comfda.govnih.gov While the maximum plasma concentrations of this compound and its active metabolite are approximately equal, the area under the plasma concentration-time curve (AUC) of the metabolite is about four times greater than that of this compound. fda.govnih.gov In addition to the active metabolite, several inactive metabolites are also formed during the metabolism of this compound. fda.gov

Excretion Pathways

This compound and its metabolites are eliminated from the body through both renal and hepatic pathways. wikipedia.orgdroracle.ainih.gov Following oral administration of radiolabeled this compound, approximately 35% of the radioactivity is recovered in the urine and about 60% in the feces, indicating significant biliary excretion. medicines.org.ukdroracle.ai For the parent drug, this compound, renal excretion is a minor elimination pathway, accounting for about 12% of its plasma clearance, with approximately 4% of an oral dose excreted unchanged in the urine. fda.govdroracle.aipharmgkb.orgnih.govtaltech.ee In contrast, renal excretion is a major pathway for the active metabolite, EXP3174, accounting for about 55% of its plasma clearance, with approximately 6% of an oral dose of this compound excreted in the urine as the active metabolite. wikipedia.orgfda.govdroracle.aipharmgkb.orgnih.govtaltech.ee The terminal elimination half-life of this compound is relatively short, ranging from 1.5 to 2.5 hours, while the active metabolite EXP3174 has a longer terminal half-life of 6 to 9 hours. wikipedia.orgmims.comfda.govpharmgkb.orgnih.govnih.gov Neither this compound nor its active metabolite accumulates in the body with repeated once-daily dosing. fda.govnih.gov

Pharmacokinetic Parameters of this compound and its Active Metabolite (EXP3174)

Key Enzymes Involved in this compound Metabolism

Metabolite Potency

Contribution of EXP3174 to Total Angiotensin II Receptor Blockade

Excretion Pathways Summary

Models of Experimental and Genetic Hypertension

This compound has been evaluated in numerous animal models of hypertension, including those with experimental and genetic origins. In stroke-prone spontaneously hypertensive (SHRSP) rats, early and long-term treatment with this compound effectively reduced the progression from prehypertension to established hypertension. nih.govahajournals.org this compound treatment in L-NAME-induced hypertensive rats, a model of severe arterial hypertension induced by nitric oxide synthase inhibition, attenuated the rise in blood pressure. ekb.eg While this compound significantly reduced systolic blood pressure in this model, the pressure remained partly elevated compared to control groups. ekb.eg Studies in juvenile spontaneously hypertensive rats also demonstrated that this compound can significantly reduce systolic and diastolic blood pressure. mdpi.com

Mechanisms of Cardiovascular Remodeling and Hypertrophy Regression

Preclinical research has highlighted this compound's beneficial effects on cardiovascular remodeling and hypertrophy. In SHRSP rats, this compound treatment improved vascular remodeling and function, which was associated with decreased AT1R and increased AT2R vascular expression. nih.gov Long-term this compound administration in SHRSP rats prevented the development of left ventricular hypertrophy. ahajournals.org

Studies in an Adriamycin-induced cardiomyopathy rat model showed that this compound reduced left ventricular hypertrophy and fibrosis. jchestsurg.org this compound treatment decreased the expression of markers associated with cardiac injury, remodeling, and apoptosis, such as collagen 1, TNF-α, and MMP-2, in this model. jchestsurg.org The renin-angiotensin system plays a crucial role in cardiac remodeling, and Ang II, acting through the AT1 receptor, is a potent growth factor in the heart. jchestsurg.org this compound, by blocking AT1R, prevents the actions of Ang II and has been shown to inhibit inflammatory, fibrogenic, and apoptotic pathways. jchestsurg.org

In the L-NAME-induced hypertension model, this compound was used to investigate the involvement of the renin-angiotensin system in hypertension and cardiac remodeling. ekb.eg this compound largely attenuated the L-NAME induced hypertension and was associated with amelioration of cardiac hypertrophy and remodeling. ekb.eg

Assessment in Heart Failure Models

This compound has been assessed in various animal models of heart failure. In a rat myocardial infarction (MI) model, this compound treatment reduced filling pressure and resulted in smaller left ventricular volumes compared to untreated controls. oup.com This aligns with the understanding that Ang II contributes to increased afterload and preload in heart failure, leading to decreased cardiac output. oup.com

In a genetic model of heart failure using transgenic mice with selective overexpression of calsequestrin, this compound treatment reduced mortality, relative heart weight (indicating reduced hypertrophy), and the degree of fibrosis. nih.gov this compound also improved hemodynamic parameters in this model, such as left ventricular pressure and its first derivative. nih.gov These findings suggest that AT1 receptor activation contributes to heart failure in this model, and its blockade with this compound is beneficial. nih.gov

However, in a doxorubicin-induced chronic cardiotoxicity rat model, this compound treatment improved diastolic but not systolic dysfunction and ameliorated SERCA2a repression. mdpi.com While this compound significantly reduced the overexpression of inflammatory markers like Il1 and Il6, it did not significantly reduce left ventricular fibrosis in this specific model. mdpi.com

Stroke Prevention and Neuronal Damage Limitation in Ischemic Models

Preclinical studies have explored the potential of this compound in stroke prevention and limiting neuronal damage in ischemic models. In rodent models of ischemic stroke, this compound pretreatment has demonstrated beneficial effects on cerebral tolerance to ischemic injury. openaccessjournals.com this compound reduced neuronal damage in the CA1 region following global ischemia and decreased infarct volume following transient focal ischemia (MCAO). openaccessjournals.com These protective effects were observed even with reductions in blood pressure. openaccessjournals.com

In human renin and angiotensinogen double-transgenic mice, which exhibit enhanced ischemic brain damage, treatment with this compound abolished the exaggeration of cell injury induced by oxygen and glucose deprivation in brain slices. nih.gov This indicates that the activation of Ang II/AT1 signaling is detrimental to the brain during ischemia, and this compound's blockade of AT1 receptors is protective. nih.gov

This compound has also shown neuroprotective effects in traumatic brain injury (TBI) mouse models, reducing brain lesion volume and neuronal apoptosis. frontiersin.org It was found to enhance blood-brain barrier integrity and improve neurological and motor function. frontiersin.org Mechanistically, this compound treatment decreased ER stress proteins and inhibited pro-inflammatory factors while increasing anti-inflammatory factors. frontiersin.org

Further studies suggest that this compound's neuroprotective effects might involve mechanisms beyond simple AT1 receptor blockade, potentially influencing pathways related to inflammation and amyloid-beta metabolism and clearance. researchgate.net

Anti-fibrotic Effects in Hepatic Disease Models

Preclinical research has demonstrated the anti-fibrotic potential of this compound in models of hepatic disease. Studies in animal models of liver fibrosis, such as those induced by Concanavalin A (Con A) in mice, have shown that this compound can prevent liver fibrogenesis and downregulate the expression of transforming growth factor-beta 1 (TGF-β1). oatext.com this compound has also been observed to inhibit the activation and proliferation of hepatic stellate cells (HSCs), which are key mediators of liver fibrosis. oatext.com The renin-angiotensin system is implicated in liver fibrogenesis through the activation of HSCs, and this compound, as an AT1R antagonist, appears to prevent fibrosis by suppressing TGF-β1 expression. oatext.com

Further studies using a model of advanced hepatic fibrosis induced by prolonged Thioacetamide (TAA)/ethanol treatment in mice demonstrated that this compound-loaded hyaluronic acid (HA) micelles significantly attenuated hepatic fibrosis. plos.org This effect was achieved through an HSC-targeting mechanism. plos.org Treatment with this compound-HA micelles resulted in significantly lower serum enzyme levels (AST, ALT, CK, and LDH) and reduced collagen deposition compared to treatment with oral this compound. plos.org Histological analysis in this model showed that while the oral this compound group still exhibited bridging fibrosis, the this compound-HA micelle group demonstrated only septal fibrosis, indicating improved attenuation of fibrosis. plos.org

In other animal models, this compound has been reported to inhibit CCl4-induced liver fibrosis and attenuate steatohepatitis in rats. oatext.comresearchgate.net The suppression of the profibrotic cytokine TGF-β was observed following this compound administration in a choline-deficient L-amino acid-defined diet-induced steatohepatitis rat model. researchgate.net

Table 1: Effects of this compound in Hepatic Fibrosis Models

Modulation of Tissue Renin-Angiotensin System (tRAS) in Intervertebral Disc Degeneration

Research has identified the presence of a tissue renin-angiotensin system (tRAS) within human intervertebral discs (IVDs), and its components have been associated with inflammatory and degenerative processes. nih.govmdpi.comresearchgate.net Preclinical studies have investigated the impact of this compound, as an AT1R antagonist, on IVD degeneration by modulating the tRAS. mdpi.comuni-freiburg.de

In human nucleus pulposus (NP) cells, the core cells of the intervertebral disc, this compound has demonstrated anti-inflammatory and anti-degenerative effects. nih.govmdpi.com Studies using a TNF-α-induced inflammation and degeneration model in human NP cells showed that this compound significantly impaired the TNF-α-induced increase of pro-inflammatory markers (nitric oxide and TNF-α), catabolic markers (matrix metalloproteinases), and tRAS components (AGTR1a and angiotensin-converting enzyme). mdpi.com Furthermore, this compound helped maintain the NP cell phenotype by upregulating aggrecan and downregulating collagen type I expression. mdpi.com These findings suggest that tRAS signaling plays a role in IVD degeneration, and modulating tRAS with this compound could be a potential therapeutic approach. mdpi.comuni-freiburg.de

The degenerated IVD tissue has been shown to have excessively activated tRAS, and locally activated tRAS can induce NP cell senescence, apoptosis, oxidative stress, and inflammatory reactions, thereby promoting IVD degeneration. nih.gov The consistent changes observed between increased Ang II and IVD degeneration in human tissue suggest a close correlation between tRAS and IDD. nih.gov

Table 2: Effects of this compound on Human Nucleus Pulposus Cells in vitro

Anticalcification Effects in Bioprosthetic Heart Valve Models

Degenerative calcification is a major factor contributing to the failure of bioprosthetic heart valves (BHVs). koreamed.orgfrontiersin.org Preclinical studies have explored the potential of this compound to attenuate calcification in BHV models.

In a rabbit intravascular implant model using bovine pericardial tissue, this compound significantly attenuated post-implant degenerative calcification. nih.govoup.comoup.com The calcium measurement level in the this compound-treated group was significantly lower compared to the control group after 6 weeks. nih.govoup.comoup.com Investigations into the mechanisms revealed that this compound suppressed the expression of key proteins involved in calcification, including interleukin-6 (IL-6), osteopontin, and bone morphogenetic protein 2 (BMP-2). nih.govoup.comoup.com Immunohistochemistry analyses also showed that BMP-2-positive reactions were significantly attenuated in the this compound group. nih.govoup.comoup.com

Another comparative study in a rabbit model of intravascular BHV leaflet implantation showed that this compound had a lower calcium content compared to the control group, although a grape seed extract (Entelon150®) showed a tendency for even lower calcium content. koreamed.orgresearchgate.net These studies suggest that this compound may exert anticalcification effects on BHV tissue. koreamed.orgnih.govoup.comoup.comresearchgate.net

Table 3: Anticalcification Effects of this compound in Rabbit BHV Model

Central and Peripheral Sympathetic Nervous System (SNS) Activity Inhibition

This compound has been investigated for its effects on sympathetic nervous system (SNS) activity in preclinical models. Angiotensin II is known to stimulate both central and peripheral SNS activity. nih.govahajournals.org

Studies in a rat model of neurogenic hypertension induced by intrarenal phenol injection demonstrated that this compound prevented the rise in blood pressure and SNS activity. nih.govahajournals.org Central SNS activity, measured by norepinephrine secretion from the posterior hypothalamic nuclei (PH), and peripheral SNS activity, measured by renal sympathetic nerve activity (RSNA), were inhibited by this compound in a dose-dependent manner when administered intravenously or in the lateral ventricle. nih.govahajournals.org this compound also caused a dose-dependent rise in the abundance of interleukin-1 beta (IL-1β) and neuronal nitric oxide synthase (nNOS) mRNA in brain regions involved in the noradrenergic control of blood pressure (PH, paraventricular nuclei (PVN), and locus ceruleus (LC)), which were decreased by phenol injection. nih.govahajournals.org These findings suggest that this compound's antihypertensive action in this model is largely mediated by the inhibition of central and peripheral SNS activity, potentially through modulating IL-1β and nNOS. nih.govahajournals.org

Another study in rats with mild chronic renal failure showed that this compound modulated central neuronal activation, particularly inhibiting Fos-activity in locus coeruleus neurons, a brain area involved in central sympathetic outflow. plos.org This indicates that this compound can ameliorate the increased activity in central sympathetic and stress-related brain areas observed in this model. plos.org

Table 4: Effects of this compound on Sympathetic Nervous System Activity in Rat Models

Hypertension Management and Blood Pressure Control

This compound is an established treatment for essential hypertension. Clinical trials have shown its effectiveness in lowering blood pressure, both when used as monotherapy and in combination with other antihypertensive agents like hydrochlorothiazide (HCTZ). In studies involving patients with mild to moderate essential hypertension, this compound 50 mg once daily demonstrated similar antihypertensive effects to enalapril 20 mg once daily. This compound 50 to 100 mg once daily also showed comparable effects to felodipine 5 to 10 mg and atenolol 50 to 100 mg once daily. nih.gov The addition of HCTZ to this compound has been shown to produce further significant reductions in blood pressure. nih.gov

Studies indicate that this compound can begin to lower blood pressure within hours of the first dose. consensus.app In patients with essential hypertension, this compound 50 mg daily significantly reduced mean arterial pressure after one month of treatment. consensus.app Long-term studies have shown that this compound maintains its efficacy for extended periods, contributing to sustained blood pressure control. consensus.app

Comparative studies have indicated that this compound is as effective as other antihypertensive agents in reducing blood pressure. consensus.app For instance, in one trial, this compound 50 mg daily produced blood pressure reductions comparable to enalapril 20 mg daily after 8 weeks. consensus.app Another study comparing various doses of this compound (10, 25, 50, 100, and 150 mg) with enalapril 20 mg and placebo in patients with mild to moderate essential hypertension found that this compound 50 to 150 mg and enalapril 20 mg produced clinically significant reductions in blood pressure after 8 weeks. ahajournals.org The trough antihypertensive efficacy of this compound 50 mg was approximately the same as enalapril 20 mg. ahajournals.org

Data from a study evaluating the effects of this compound on serum uric acid levels in essential hypertension also reported a statistically significant reduction in mean systolic blood pressure from 146 to 127 mmHg and mean diastolic blood pressure from 92 to 82 mmHg after 6 months of this compound therapy. impactfactor.org

Heart Failure Management, particularly with Reduced Left Ventricular Ejection Fraction

The HEAAL study, a randomized, double-blind trial, compared the effects of high-dose (150 mg daily) versus low-dose (50 mg daily) this compound on clinical outcomes in patients with heart failure, reduced left-ventricular ejection fraction, and intolerance to ACE inhibitors. nih.gov The study found that this compound 150 mg daily reduced the rate of death or admission for heart failure compared with this compound 50 mg daily in this patient population. nih.gov

A network meta-analysis of studies on drug treatments for chronic heart failure with reduced ejection fraction suggested that while ARB monotherapy did not show a significant reduction in all-cause mortality compared to placebo, combinations of therapies including ARBs demonstrated better outcomes. ahajournals.org

Stroke Risk Reduction in Patients with Hypertension and Left Ventricular Hypertrophy

This compound has demonstrated efficacy in reducing the risk of stroke in specific patient populations, particularly those with hypertension and left ventricular hypertrophy (LVH). The this compound Intervention For Endpoint reduction in hypertension (LIFE) study, a landmark trial, compared this compound-based treatment with atenolol-based conventional therapy in hypertensive patients with electrocardiographic evidence of LVH. nih.govahajournals.orgwikijournalclub.orgjournals.co.za

Secondary analyses of the LIFE study indicated that the cerebrovascular benefits of this compound applied to different clinical subgroups and stroke subtypes. nih.govahajournals.org The reduction in fatal stroke (hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.43 to 0.96; P=0.032) and atherothrombotic stroke (HR, 0.72; 95% CI, 0.59 to 0.88; P=0.001) with this compound compared to atenolol was statistically significant. nih.govahajournals.org The benefits of this compound on all strokes were independent of baseline and time-varying risk factors, including blood pressure. nih.govahajournals.org The number needed to treat for 5 years to prevent 1 stroke was 54 for the average participant in the LIFE study. nih.govwikijournalclub.org

Diabetic Nephropathy Progression Prevention

This compound has been shown to slow the progression of renal disease in patients with type 2 diabetes and nephropathy. The Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist this compound (RENAAL) study, a large randomized, double-blind trial involving 1513 patients with type 2 diabetes and proteinuria, evaluated the effects of this compound compared to placebo, both in addition to conventional antihypertensive treatment. nih.govnih.gov2minutemedicine.comconsensus.app

Over a mean follow-up of 3.4 years, this compound significantly reduced the incidence of the primary composite endpoint (doubling of baseline serum creatinine concentration, end-stage renal disease, or death) by 16% (P=0.02). nih.govnih.gov2minutemedicine.com this compound specifically reduced the incidence of a doubling of serum creatinine concentration by 25% (P=0.006) and end-stage renal disease by 28% (P=0.002) compared to placebo. nih.govnih.gov2minutemedicine.comresearchgate.net The renal benefits observed with this compound in the RENAAL study exceeded those attributable solely to changes in blood pressure. nih.govresearchgate.net

While the RENAAL study demonstrated significant benefits in slowing the progression to ESRD, it did not show a significant effect on the rate of death. nih.govnih.gov2minutemedicine.com

The efficacy of ARBs, including this compound, in the primary prevention of diabetic kidney disease in normoalbuminuric patients is less certain and requires further investigation. nih.govopenaccessjournals.com

Reduction of Proteinuria and Albuminuria

A key renoprotective effect of this compound is its ability to reduce proteinuria and albuminuria, markers of kidney damage. In the RENAAL study, this compound treatment led to a significant reduction in the level of proteinuria by 35% compared to placebo (P<0.001). nih.govresearchgate.net This reduction in proteinuria is considered an important factor in the observed slowing of renal disease progression. kidney.org

Studies have also investigated the effect of this compound on microalbuminuria in normotensive patients with type 2 diabetes. A randomized controlled trial found that this compound significantly reduced albuminuria in this population, and this anti-albuminuric effect was observed to be independent of the associated reduction in blood pressure. nih.govnih.gov

In a study of children aged 1 to 17 years with proteinuria, with or without hypertension, this compound treatment for 12 weeks significantly reduced proteinuria compared with amlodipine or placebo. nih.gov The study reported a 35.8% reduction in mean urinary protein-creatinine ratio with this compound. nih.gov Proteinuria reduction was consistently observed in both normotensive and hypertensive strata. nih.gov

Another study in diabetic and non-diabetic patients with daily urinary protein excretion >500 mg showed that this compound monotherapy was effective in reducing daily urinary protein excretions. karger.com In this study, 64% of patients had a more than 25% decrease in their daily urinary protein excretion, with a mean decrease of 57%. karger.com

The reduction in albuminuria with this compound has been shown to be related to changes in cardiovascular risk in hypertensive patients with LVH, suggesting that changes in albuminuria translate to changes in risk. ahajournals.org

Table 1: Summary of Key Clinical Trial Findings on this compound Efficacy

Impact on End-Stage Renal Disease (ESRD) Incidence and Serum Creatinine Levels

This compound, an angiotensin II AT(1) receptor antagonist, has demonstrated significant renal benefits, particularly in patients with type 2 diabetes mellitus and proteinuria. A pivotal trial, the Reduction of Endpoints in Non insulin dependent diabetes mellitus with the Angiotensin II Antagonist this compound (RENAAL) study, involving 1513 patients, showed that this compound significantly reduced the incidence of a doubling of serum creatinine, end-stage renal disease (ESRD), or death compared to placebo. nih.govnih.gov Specifically, this compound was associated with a 16% reduction in the primary composite endpoint (doubling of serum creatinine concentration, ESRD, or death) (p = 0.022) and a 29% reduction in the risk of ESRD alone (p = 0.002). nih.gov this compound also significantly reduced the incidence of doubling of serum creatinine level (p = 0.006), ESRD (p = 0.002), ESRD or death (p = 0.01), and doubling of serum creatinine and ESRD (p = 0.01) compared with placebo in the RENAAL trial. nih.gov

Data from several studies indicate that this compound effectively reduces the mean albumin excretion rate. nih.gov Two double-blind studies have shown that this compound has similar effects to enalapril on kidney function. nih.gov In hypertensive patients with non-diabetic nephropathy, this compound has been found to significantly reduce proteinuria, a crucial factor in slowing the progression of kidney disease. consensus.app this compound also decreased the filtration fraction in these patients, indicating improved renal hemodynamics. consensus.app

An interesting observation from the RENAAL trial was that an acute fall in estimated glomerular filtration rate (eGFR) during the initial phase of this compound treatment predicted a slower decline in long-term renal function. consensus.app Patients who experienced a significant initial drop in eGFR had a slower rate of eGFR decline over time, suggesting this initial response might be a favorable prognostic indicator. consensus.app

The economic evaluation of the RENAAL study revealed that this compound not only reduced the incidence of ESRD but also resulted in substantial cost savings. consensus.app Patients treated with this compound experienced fewer days with ESRD, leading to a net savings of $3522 per patient over 3.5 years. consensus.app This underscores the cost-effectiveness of this compound in managing diabetic nephropathy. consensus.app

Note: Data in the table is derived from the RENAAL study. Some specific percentage reductions for individual endpoints beyond the composite were not available in the provided snippets, hence marked as N/A.

Investigations in Cancer Therapies

Research has investigated the potential role of this compound in cancer therapies, particularly in improving the effectiveness of chemotherapy agents. massgeneral.orgecancer.orgharvard.edu Studies have found that this compound may improve the effectiveness of chemotherapy agents used to treat ovarian cancer. ecancer.orgharvard.edu Previous research identified a similar effect for this compound in animal models of breast and pancreatic cancer, leading to a phase 2 clinical trial with promising results against pancreatic cancer. ecancer.orgharvard.edu

In patients with locally advanced pancreatic cancer, treatment with a combination therapy including this compound inhibited immunosuppression and reduced the expression of genes that promote the invasion of tumor cells into normal tissue. massgeneral.orgharvard.edu this compound also induced changes in the blood levels of various molecules involved in blood vessel health and the immune response. massgeneral.orgharvard.edu Tumor tissue from patients treated with this compound in combination therapy showed decreased numbers of cells that suppress the immune response and higher numbers of immune cells important for killing cancerous or virally infected cells. massgeneral.orgharvard.edu These findings suggest that this compound may potentiate the benefit of chemotherapy by reducing tumor invasion and immunosuppression. massgeneral.orgharvard.edu

Clinical trials are currently evaluating the effectiveness of adding this compound to different cytotoxic treatment regimens or cytotoxics plus immunotherapy in patients with pancreatic cancer. massgeneral.orgharvard.edu These trials aim to determine if this compound, when combined with different therapies, can improve treatment response and long-term survival in pancreatic cancer patients. massgeneral.orgharvard.edu

This compound has also been investigated in other cancer types. For instance, a clinical study is evaluating the effect of this compound on the response rate in both metastatic and locally advanced pancreatic cancer patients. careacross.com Other ongoing clinical trials involving this compound include studies for relapsed or refractory osteosarcoma, and locally recurrent, refractory, or oligometastatic head and neck squamous cell carcinoma. cancer.gov Research also suggests that this compound could enhance the radiosensitivity of triple-negative breast cancer by reshaping the tumor immune microenvironment in an immune system-dependent way. aacrjournals.org

Neurological Disorder Research (e.g., Alzheimer's disease, TBI)

This compound has been explored for its potential therapeutic value in neurological disorders, including Alzheimer's disease (AD) and traumatic brain injury (TBI). Research suggests that this compound may slow down the progression of AD by improving brain blood flow and altering chemical pathways that affect abnormal proteins accumulating in the brain. isrctn.com this compound has shown promise in improving memory problems in mice models with Alzheimer's features and in individuals given chemicals to temporarily affect their memories. isrctn.com

However, a randomized, double-blind, placebo-controlled phase 2 clinical trial (the RADAR trial) investigating this compound in patients with mild-to-moderate Alzheimer's disease found that this compound was ineffective in reducing the rate of total brain atrophy and the volume of white matter hyperintensities over 12 months. eanpages.orgstepupfordementiaresearch.org.aunihr.ac.uk While the drug was well-tolerated, the study did not show a significant difference between the this compound and placebo groups in slowing the progression of AD as measured by whole brain shrinkage on MRI scans. stepupfordementiaresearch.org.aunihr.ac.uk The researchers suggested that further studies are needed to explore the potential therapeutic effect of this compound in patients with milder cognitive impairment or when administered for longer periods. eanpages.org

Some studies have suggested that individuals who have previously taken this compound may have a lower risk of developing AD compared to those taking other blood pressure medications. isrctn.com These drugs may also slow the rate of deterioration in patients with Alzheimer's. isrctn.com

Ocular Applications

Topical this compound has been explored for its potential in treating various eye diseases and disorders, particularly those involving scarring fibrosis, where TGF-beta plays a central role in pathophysiology. nih.govresearchgate.net Studies have supported the efficacy of topical this compound in decreasing scarring fibrosis after corneal injuries such as Descemetorhexis, alkali burns, and photorefractive keratectomy in animal models. nih.govresearchgate.net Case reports in humans have also suggested its benefit in managing scarring fibrosis after surgical complications. nih.gov

This compound is known to impede TGF-beta signaling by inhibiting the activation of extracellular signal-regulated kinase (ERK). nih.govclevelandclinic.org This mechanism is believed to contribute to its ability to prevent or reverse scarring in the anterior segment of the eye, including the conjunctiva in fibrotic diseases of that tissue. clevelandclinic.org Research suggests that topical this compound may be effective in treating conditions like ocular cicatricial pemphigoid and Stevens-Johnson syndrome. nih.gov

Investigations are also exploring the efficacy and safety of topical this compound treatments to reduce conjunctival bleb scarring and shunt encapsulation following glaucoma surgical procedures. nih.gov this compound, potentially delivered via sustained-release devices, could also be efficacious in treating intraocular fibrotic diseases. nih.gov

While lower concentrations of topical this compound have shown promise, research in rabbit eyes suggests that higher doses may lead to increased ocular toxicity and discomfort, with adverse effects observed at concentrations significantly higher than typically explored for therapeutic benefit. reviewofoptometry.com

Musculoskeletal System and Bone Health

This compound's effects on the musculoskeletal system and bone health have also been investigated. Preclinical studies have reported benefits of this compound on bone fracture healing and reduction in bone fracture risk. scielo.br Studies have shown that this compound can enhance bone density by decreasing osteoclastogenesis and increasing osteoblastic activity. scielo.br

Research in animal models has explored the influence of this compound on alveolar bone dynamics. scielo.br One study showed a positive effect of this compound on alveolar bone dynamics in normotensive animals, with higher calcium marking and increased parameters of bone formation. scielo.br However, this anabolic effect was not observed in hypertensive models. scielo.br

In the context of musculoskeletal injuries, this compound has shown potential in reducing scar tissue formation and improving functional muscle recovery when used with muscle-derived stem cells in a murine model. amegroups.org Initial findings are also promising regarding the benefits of this compound in tendon repair, with studies suggesting increased tensile strength and improved tendon morphology in rabbits. amegroups.org

This compound has also been investigated in the genetic disorder Osteogenesis Imperfecta (OI), which is characterized by bone fragility. A clinical study is aiming to determine if reducing circulating TGF-beta levels with this compound can reduce bone turnover and bone loss and have a positive effect on muscle function and quality of life in older adolescents and adults with OI. isrctn.com

Cytochrome P450 Enzyme System Interactions (e.g., CYP2C9, CYP3A4)

This compound is metabolized to its more potent active metabolite, E-3174, mainly by the cytochrome P450 enzymes CYP2C9 and CYP3A4. consensus.appkarger.compharmgkb.org CYP2C9 appears to be the more significant enzyme in this biotransformation in vivo. karger.compharmgkb.org

Interactions can occur when this compound is coadministered with drugs that inhibit or induce these enzymes. Inhibitors of CYP2C9 or CYP3A4 can decrease the metabolism of this compound to E-3174, potentially reducing its antihypertensive effect. Conversely, inducers of these enzymes could theoretically increase the conversion of this compound to its active metabolite, although this is less commonly a clinical concern.

Studies have shown that while both CYP2C9 and CYP3A4 are involved, the relative contribution can vary. In vitro studies suggested a significant role for CYP3A4, but in vivo studies emphasize the prominent role of CYP2C9. pharmgkb.org For example, fluconazole, a CYP2C9 inhibitor, has been shown in vitro to significantly decrease the formation of E-3174. nih.gov However, some in vivo studies with CYP3A4 inhibitors like itraconazole, erythromycin, and cimetidine have not shown significant effects on this compound pharmacokinetics, suggesting that inhibition of both pathways might be needed for a significant change. pharmgkb.org

This compound itself has been reported to have inhibitory effects on CYP2C9, which could affect the metabolism of other drugs metabolized by this enzyme, such as glimepiride. karger.com

Interactions Affecting Serum Potassium Levels (e.g., Potassium-Sparing Diuretics, NSAIDs)

Concomitant use of this compound with agents that increase serum potassium levels can lead to hyperkalemia. nih.govsinglecare.com this compound, by blocking the effects of angiotensin II, reduces aldosterone secretion, which can lead to decreased potassium excretion. pediatriconcall.com

Potassium-sparing diuretics, such as spironolactone, eplerenone, and triamterene, are known to increase serum potassium levels by different mechanisms in the renal tubules. singlecare.comgoodrx.comnih.govpatient.info Combining these with this compound significantly increases the risk of hyperkalemia. singlecare.comgoodrx.comnih.govpatient.info Regular monitoring of serum potassium levels is recommended when these medications are coadministered. nih.govsinglecare.comgoodrx.compatient.info

Nonsteroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors, can also interact with this compound, affecting both blood pressure and renal function. nih.govgoodrx.comhealthline.commedicalnewstoday.commedicalnewstoday.com NSAIDs can reduce the antihypertensive effects of ARBs like this compound. nih.govmedicalnewstoday.commedicalnewstoday.com Furthermore, in patients who are elderly, volume-depleted, on diuretic therapy, or have impaired renal function, the coadministration of NSAIDs with this compound may lead to a decline in renal function, including acute kidney injury. nih.govgoodrx.comhealthline.commedicalnewstoday.commedicalnewstoday.com This effect is often reversible. nih.gov Periodic monitoring of renal function is advised when this compound is used with NSAIDs. nih.govmedicalnewstoday.com

Dual blockade of the renin-angiotensin system (RAS) by combining this compound with ACE inhibitors or direct renin inhibitors (e.g., aliskiren) is associated with increased risks of hypotension, syncope, hyperkalemia, and acute kidney injury compared to monotherapy. nih.govsinglecare.comgoodrx.com The coadministration of aliskiren with this compound is generally not recommended, especially in patients with diabetes or renal impairment (GFR < 60 mL/min). nih.govsinglecare.comgoodrx.com

Concomitant Use with Lithium

Simultaneous use of lithium and ARBs, including this compound, has been associated with elevated serum lithium concentrations and toxicity. nih.govhealthline.commedicalnewstoday.comdroracle.aiontosight.aidrugs.comresearchgate.net The mechanism is believed to involve the effect of this compound on renal function, specifically by decreasing renal clearance of lithium. droracle.aiontosight.aidrugs.comresearchgate.net this compound's effect on renal blood flow and potential for natriuresis can enhance the reabsorption of lithium in the renal tubules, leading to increased serum levels. ontosight.aidrugs.comresearchgate.net Regular monitoring of serum lithium levels is strongly recommended when this compound and lithium are used together. nih.govhealthline.com

Interactions with Herbal Supplements and Dietary Components (e.g., Grapefruit Juice)

Certain herbal supplements and dietary components can interact with this compound. Supplements containing potassium, similar to potassium-sparing diuretics, can increase the risk of hyperkalemia when taken with this compound. singlecare.comhealthline.compeacehealth.org Examples of herbal supplements that may contain potassium include chicory, ginseng, lemongrass, water lotus, and mugwort. singlecare.com Salt substitutes that are high in potassium should also be used with caution or avoided. singlecare.comdrugs.compeacehealth.orgwww.nhs.uk

Grapefruit and grapefruit juice have been shown to interact with this compound, although the clinical significance can vary. www.nhs.ukdrugs.comconsensus.apphealthline.comwellrx.com Grapefruit juice is known to inhibit CYP3A4 in the gut wall, which can affect the metabolism of drugs metabolized by this enzyme. consensus.app While this compound is metabolized by both CYP2C9 and CYP3A4, grapefruit juice's inhibition of CYP3A4 can lead to decreased conversion of this compound to its active metabolite, E-3174. consensus.appwellrx.com This could potentially decrease the efficacy of this compound in some patients. drugs.comhealthline.comwellrx.com Some sources advise avoiding grapefruit and grapefruit juice while taking this compound due to this potential interaction. www.nhs.ukdrugs.comwellrx.com

Herbal supplements like Nigella sativa have shown potential interactions by enhancing the antihypertensive effect of this compound in animal studies, possibly due to inhibitory effects on CYP3A4 and CYP2C9. nih.gov Berberine has also demonstrated inhibitory effects on CYP2D6, CYP3A4, and CYP2C9, suggesting a potential herb-drug interaction with this compound. nih.gov Garlic supplements may also impact the bioavailability of this compound due to effects on intestinal absorption and liver metabolism. nih.gov Due to limited and sometimes contradictory information, caution is advised regarding the coadministration of this compound with herbal supplements, and patients should inform their healthcare providers about all supplements they are taking. healthline.comwww.nhs.uk

Genetic Polymorphisms Influencing Antihypertensive Efficacy

Genetic variations in enzymes involved in this compound metabolism, such as CYP2C9, can impact its conversion to the active metabolite E-3174, which is more potent than the parent compound. frontiersin.orgdergipark.org.trnih.gov Polymorphisms in the CYP2C9 gene, particularly the CYP2C92 and CYP2C93 alleles, are known to result in decreased enzyme activity. dergipark.org.trnih.govpharmgkb.org

Studies have investigated the effect of these polymorphisms on this compound pharmacokinetics and pharmacodynamics. Carriers of the CYP2C92 or CYP2C93 alleles generally exhibit higher plasma concentrations of this compound and lower concentrations of the active metabolite E-3174 compared to individuals with the wild-type CYP2C91/CYP2C91 genotype. nih.govpharmgkb.org This altered metabolic profile can lead to a diminished antihypertensive response to this compound in individuals with these reduced-function alleles. frontiersin.orgdergipark.org.trnih.gov

For example, studies have shown that subjects with the CYP2C91/CYP2C93 genotype had a significantly higher urinary this compound/E-3174 ratio and a less pronounced hypotensive effect compared to those with the CYP2C91/CYP2C91 genotype. nih.govpharmgkb.org While some studies have shown a trend towards a reduced systolic blood pressure response in carriers of the CYP2C91/CYP2C92 genotype, this has not always reached statistical significance. dergipark.org.tr The impact of CYP2C9 polymorphisms on this compound response can vary depending on ethnicity and study population characteristics. pharmgkb.orgnih.gov

Beyond metabolic enzymes, genetic variations in components of the renin-angiotensin system itself can also influence the response to this compound. Polymorphisms in the angiotensin II type 1 receptor gene (AGTR1), the target of this compound, have been studied. For instance, the AGTR1 A1166C polymorphism (rs5186) has been associated with varying responses to this compound. Studies suggest that individuals carrying the C allele (AC or CC genotypes) may have a better humoral and renal hemodynamic response to this compound compared to those with the AA genotype, exhibiting greater decreases in mean arterial pressure and aldosterone levels. pharmgkb.org

Polymorphisms in other genes involved in blood pressure regulation have also been explored. A study in an older Chinese population found that a genetic variant (-1860T>C) in the apelin promoter was associated with the blood pressure response to this compound, with women carrying the TT genotype showing a greater reduction in systolic blood pressure. geneticsmr.org

Furthermore, polymorphisms in drug transporters, such as the efflux transporter MDR1 (ABCB1), for which this compound is a substrate, have been investigated for their potential influence on this compound response. europeanreview.org One study found that the MDR1 C3435T genetic polymorphism was associated with a higher systolic blood pressure response to this compound in hypertensive patients, with carriers of the mutant allele (CT/TT) showing a significantly better clinical response compared to those with the CC genotype. europeanreview.org

These findings highlight the complex interplay between genetic factors and this compound's effectiveness, suggesting that pharmacogenomic profiling could potentially help personalize antihypertensive therapy in the future.

Pharmacogenomic Determinants of this compound Response

Genetic Variations Affecting Drug Bioactivation and Metabolism

This compound undergoes significant first-pass metabolism after oral administration, resulting in a bioavailability of approximately 33%. nih.gov The primary metabolic pathway involves the oxidation of this compound to the more potent carboxylic acid metabolite, E-3174. pharmgkb.orgnih.gov This bioactivation step is mainly catalyzed by the CYP2C9 enzyme, with contributions from CYP3A4. pharmgkb.org

The CYP2C9 gene is highly polymorphic, with numerous variants identified that can alter enzyme activity. nih.govfrontiersin.org The most extensively studied of these are the CYP2C9 *2 (rs1799853) and *3 (rs1057910) alleles, which are associated with decreased enzyme activity compared to the wild-type *1 allele. pharmgkb.orgnih.gov Studies have shown that individuals carrying CYP2C9 *2 or *3 alleles exhibit reduced metabolism of this compound to E-3174. nih.gov

Research indicates that the rate of this compound oxidation is lower in liver microsomes from individuals who are hetero- or homozygous for the CYP2C9 3 allele, or homozygous for the CYP2C9 *2 allele. pharmgkb.org This reduced conversion to the active metabolite can lead to altered pharmacokinetic profiles. For instance, carriers of CYP2C9 *2 or *3 alleles tend to have a higher area under the curve (AUC) for this compound and a lower AUC for E-3174 compared to individuals with the CYP2C9 *1/1 genotype. nih.gov While some studies have shown no significant difference in the maximum concentration (Cmax) of this compound across these genotypes, carriers of CYP2C9 *2 or *3 typically have lower Cmax values for E-3174. nih.gov The half-lives of both this compound and E-3174 may also be longer in carriers of these variant alleles. nih.gov

The impact of these genetic variations on the clinical response to this compound has been investigated, although findings can be variable. Some studies suggest that the CYP2C9 3 variant may reduce this compound metabolism and its hypotensive effect. nih.gov For example, one study observed that subjects with the CYP2C9 *1/3 genotype had a lower Cmax of E-3174 and a less pronounced hypotensive effect compared to those with the CYP2C9 1/1 genotype. nih.gov However, other studies have not found a significant influence of CYP2C9 *2 and *3 alleles on the antihypertensive effect of this compound in certain populations. pharmgkb.org

Beyond CYP2C9, other genetic factors may also play a role. This compound has been identified as a substrate for the ABCB1 (MDR1) transporter in in vitro studies, although its active metabolite E-3174 does not appear to be a substrate. europeanreview.org Some studies have explored the relationship between ABCB1 polymorphisms, such as C3435T, and the response to this compound, with some findings suggesting a potential association with clinical response, although results can be conflicting. europeanreview.org

The plasma metabolic ratio of this compound to E-3174 is considered an indirect measure of CYP2C9 activity. ajms.iqajms.iq Studies using this ratio have provided insights into the functional impact of specific CYP2C9 single nucleotide polymorphisms (SNPs). For example, the rs1799853 SNP variant has been shown to significantly impact CYP2C9 metabolic activity, resulting in a higher this compound/E-3174 metabolic ratio in carriers of the variant genotype compared to the wild-type. ajms.iqajms.iqresearchgate.net The rs1057910 SNP variant has also been studied, with some research indicating a statistically significant increase in this ratio in carriers of the variant genotype, although other studies have found the effect of rs1799853 to be more evident. ajms.iqajms.iqresearchgate.net

The following table summarizes some observed effects of CYP2C9 genotypes on this compound and E-3174 pharmacokinetics:

Note: This table summarizes general trends observed in various studies. Specific values and statistical significance may vary depending on the study population and methodology.

Pharmacogenomic Markers for Uricosuric Effects

Beyond its antihypertensive action, this compound is known to possess a uricosuric effect, meaning it can lower serum uric acid (SUA) levels by increasing uric acid excretion. rootspress.orgtandfonline.com This effect is attributed, at least in part, to the inhibition of the human urate transporter 1 (URAT1), which is responsible for reabsorbing uric acid in the renal proximal tubules. rootspress.orgtandfonline.comnih.gov

Genetic polymorphisms in genes encoding urate transporters, particularly SLC22A12 which encodes URAT1, have been investigated for their influence on this compound's uricosuric action. rootspress.orgtandfonline.commdpi.com Studies have shown that variants within the SLC22A12 gene can affect SUA levels and the clinical response to uricosuric drugs, including this compound. mdpi.com

Specific URAT1 gene polymorphisms, such as rs3825016 and rs1529909, have been suggested as potential pharmacogenomic markers for the uricosuric effects of this compound. rootspress.orgtandfonline.com Research indicates that these polymorphisms can influence the extent to which this compound decreases SUA levels. tandfonline.com For example, one study found that hypertensive patients with hyperuricemia carrying the CT+TT genotypes of URAT1 rs3825016 or the TC genotype of rs1529909 had a lower decreased value of SUA after this compound treatment compared to patients with the wild-type genotypes. tandfonline.com This suggests that these genetic variations may impact the magnitude of this compound's uricosuric effect.

Experimental observations also provide evidence for the pharmacogenomic relevance of SLC22A12 polymorphisms. A study examining the effect of loss-of-function SLC22A12 mutations on urate clearance found that neither this compound nor benzbromarone affected urate clearance in patients carrying mutant SLC22A12. mdpi.com Conversely, in individuals with the wild-type SLC22A12 allele, both drugs significantly increased urate clearance. mdpi.com

The prevalence of specific URAT1 genotypes can vary among different ethnicities, which may contribute to observed variations in the effectiveness of this compound treatment for hyperuricemia across populations. rootspress.org

Implications for Personalized Medicine Approaches

The understanding of how genetic variations influence the metabolism and effects of this compound has significant implications for the development of personalized medicine approaches in the management of hypertension and hyperuricemia. ajms.iqajms.iqjbclinpharm.orgnih.gov Interindividual variability in drug response is a major challenge in therapeutics, and pharmacogenomics, the study of how genes influence drug response, offers a pathway to tailoring treatment strategies based on an individual's genetic makeup. jbclinpharm.orgnih.govportlandpress.com

For this compound, genetic polymorphisms in drug-metabolizing enzymes like CYP2C9 can lead to variations in the exposure to the active metabolite E-3174, potentially affecting the antihypertensive response. nih.govnih.govresearchgate.net Similarly, genetic variations in urate transporters like URAT1 can influence the uricosuric effect of this compound. rootspress.orgtandfonline.com Identifying individuals who are poor metabolizers of this compound due to CYP2C9 variants, or those who may have a diminished uricosuric response due to URAT1 variants, could help optimize therapeutic outcomes.

Pharmacogenomic testing for CYP2C9 could potentially identify patients who may require adjustments in this compound therapy to achieve adequate exposure to E-3174. While the clinical significance of CYP2C9 variation on this compound's antihypertensive effect is still being fully elucidated, particularly in diverse patient populations, the impact on metabolite formation is clear. pharmgkb.orgnih.govnih.gov

Furthermore, considering URAT1 polymorphisms could aid in predicting the likelihood of a favorable uricosuric response to this compound in hypertensive patients with hyperuricemia. rootspress.orgtandfonline.com This could inform the choice of antihypertensive medication, especially when managing comorbid hyperuricemia is a clinical goal.

The integration of pharmacogenomic information into clinical practice for this compound could involve using genetic markers to stratify patients and guide treatment decisions. jbclinpharm.orgportlandpress.com This could potentially lead to improved efficacy, reduced trial-and-error prescribing, and a more individualized approach to managing blood pressure and uric acid levels. jbclinpharm.orgnih.gov However, further research, including large-scale studies in diverse populations, is needed to fully establish the clinical utility and cost-effectiveness of routine pharmacogenomic testing for this compound therapy. pharmgkb.orgnih.gov The polygenic nature of hypertension and drug response suggests that considering interactions among multiple genes within drug response pathways may also be a promising strategy for personalized therapy. dovepress.com

Controlled and Sustained Release Formulations (e.g., Microspheres, Pellets, Osmotic Tablets)

Significant effort is being directed towards developing controlled and sustained release formulations of this compound. These formulations are designed to maintain therapeutic drug concentrations over an extended period, contrasting with the pulsatile release of conventional immediate-release tablets.

Studies have explored the development of floating drug delivery systems, such as floating tablets, to increase gastric residence time and improve absorption, particularly for drugs like this compound that may have limited absorption in the lower gastrointestinal tract asianjpr.com, . These systems often utilize polymers to control the release rate and provide buoyancy asianjpr.com, .

Multiparticulate systems, such as pellets prepared by techniques like extrusion-spheronization, are also being investigated for sustained drug release and enhanced bioavailability scienceopen.com. These systems offer advantages in terms of reduced patient-to-patient variability and optimized drug distribution scienceopen.com.

Osmotic controlled release matrix tablets represent another promising strategy, utilizing osmotic pressure to drive drug release at a controlled rate over a prolonged duration ijnrd.org. Researchers are also developing controlled-release matrices using various polymers to extend the drug's half-life and achieve 24-hour drug release rates nih.gov.

Microspheres, prepared through methods like W/O emulsion solvent evaporation, have shown potential for delivering this compound in a controlled manner over several hours rjptonline.org, wisdomlib.org. Nanoporous carbon carriers are also being explored for their ability to adsorb this compound and provide either rapid or sustained drug liberation depending on the carrier's properties mdpi.com. Additionally, sublingual tablets are being developed to enhance permeation through the oral mucosa, offering an alternative route to potentially overcome issues with oral bioavailability saapjournals.org.

Strategies for Enhancing Bioavailability and Reducing Inter-Patient Variability

Enhancing the oral bioavailability of this compound, which is reported to be approximately 33% due to first-pass metabolism and inadequate absorption from the lower gastrointestinal tract, is a key focus of novel delivery system research , scienceopen.com, nih.gov. Self Micro Emulsifying Drug Delivery Systems (SMEDDS) have been investigated as a means to enhance the oral bioavailability and dissolution rate of poorly water-soluble drugs like this compound rroij.com.

Strategies to improve the solubility and dissolution rate, such as the use of solid dispersion methods with carriers like β-cyclodextrin, are being explored to enhance the potential bioavailability of this compound wisdomlib.org. Multiparticulate drug delivery systems are also considered to have the potential to decrease patient-to-patient variability and optimize drug distribution scienceopen.com. While novel delivery systems aim to mitigate some pharmacokinetic variability, research indicates that inter-patient variability in this compound plasma profiles can also be influenced by physiological differences in gastric emptying and genetic variations in drug metabolism enzymes like CYP2C9 pharmgkb.org, frontiersin.org.

Uricosuric Mechanisms and Clinical Relevance

One of the well-documented unique properties of this compound is its uricosuric effect, which is not typically observed with other ARBs ahajournals.org, consensus.app, nih.gov, medscidiscovery.com, researchgate.net, oup.com. The mechanism underlying this effect involves the inhibition of URAT1-mediated renal tubule urate reabsorption in the proximal tubule, leading to increased excretion of uric acid in the urine ahajournals.org, medscidiscovery.com, researchgate.net. This effect appears to be primarily mediated by the parent compound, this compound, rather than its active metabolite, EXP3174 ahajournals.org, researchgate.net, oup.com. The peak uricosuric effect has been observed relatively soon after administration, typically within 2 to 4 hours ahajournals.org, researchgate.net.

The clinical relevance of this compound's uricosuric property is significant, particularly for patients with co-existing hypertension and hyperuricemia or gout consensus.app, nih.gov, medscidiscovery.com. By lowering serum uric acid levels, this compound offers a dual benefit in managing both conditions simultaneously consensus.app, nih.gov. Studies suggest that the effect on uric acid contributes to this compound's renoprotective effects, with one study estimating this contribution to be approximately 22% ahajournals.org. In the this compound Intervention For Endpoint Reduction in Hypertension (LIFE) trial, the contribution of the serum uric acid effect to the cardiovascular protective effects was estimated at 29% ahajournals.org. While the uricosuric effect increases urinary uric acid concentration, it has not been associated with adverse renal consequences like uric acid nephropathy, partly due to a concurrent increase in urinary pH researchgate.net. The serum uric acid lowering effect is typically in the range of 7-15% researchgate.net, oup.com.

Further Characterization of AT1 Receptor-Independent Actions

Emerging research highlights AT1 receptor-independent actions of this compound, suggesting therapeutic potential beyond its primary mechanism. These actions are speculated to be independent of AT1 receptor blockade because they are not consistently shared by other ARBs or ACE inhibitors ahajournals.org.

One area of investigation is this compound's ability to inhibit monocyte recruitment and CCR2 signaling consensus.app, aai.org. Studies have shown that this compound and its metabolite can potently inhibit monocyte recruitment through the noncompetitive inhibition of CCL2-induced ERK1/2 activation, independent of AT1R activity aai.org. This finding suggests potential applications in cancer therapy by inhibiting tumor growth and metastasis consensus.app, aai.org.

Furthermore, this compound may act as a dual-receptor antagonist, capable of blocking vasoconstriction and platelet aggregation induced by the thromboxane A2 (TXA2) analog U46619 and displacing ligand binding to the TXA2 receptor ahajournals.org. Other suggested AT1 receptor-independent actions include anti-inflammatory and antiaggregatory mechanisms ahajournals.org.