Olmesartan (1 mg/kg, 2 mg/kg, p.o.) is dose-dependently lowered in SHR after repeated administration, with no discernible effects on body weight or food consumption over a 10-week period[1]. Mice treated with Hyd and olemesartan (5 mg/kg/d, p.o.) exhibit comparable reductions in systolic blood pressure. Treatment with olmesartan prevents cardiac hypertrophy as determined by gene expression, heart weight, cardiomyocyte cross-sectional area, and echocardiography. Treatment with omesartan reverses the downregulation of Ren-Tg mice's ACE2 and Mas receptor gene expressions, and it prevents the upregulation of NADPH oxidase (Nox)4 expression and reactive oxygen species[2].

Olmesartan medoxomil, with an IC50 of 66.2 μM, is a strong and specific inhibitor of the angiotensin AT1 receptor.

Cell Line: Human cervical cancer cell line (HeLa)
Concentration: 0.7- 5 mM
Incubation Time: 24, 48 and 72 h
Result: IC50s against HeLa cell line are 4.685 and 1.651 mM for 48 and 72 h, respectively

Absorption, Distribution and Excretion
When taken orally, the prodrug olmesartan medoxomil is rapidly absorbed in the gastrointestinal tract and metabolized to olmesartan. The esterification with medoxomil was created with the intention of increasing olmesartan bioavailability from 4.5% to 28.6%. Oral administration of 10-160 mg of olmesartan has been shown to reach peak plasma concentration of 0.22-2.1 mg/L after 1-3 hours with an AUC of 1.6-19.9mgh/L. The pharmacokinetic profile of olmesartan has been observed to be nearly linear and dose-dependent under the therapeutic range. The steady-state level of olmesartan is achieved after once a day dosing during 3 to 5 days.
The main elimination route of olmesartan is in the unchanged form through the feces. From the systemically bioavailable dose, about 10-16% is eliminated in the urine.
17 L
Total plasma clearance is 1.3 L/h and the renal clearance is 0.6 L/h.
In rats, olmesartan crossed the blood-brain barrier poorly, if at all. Olmesartan passed across the placental barrier in rats and was distributed to the fetus.
The volume of distribution of olmesartan is approximately 17 L. Olmesartan is highly bound to plasma proteins (99%) and does not penetrate red blood cells. The protein binding is constant at plasma olmesartan concentrations well above the range achieved with recommended doses.
Olmesartan medoxomil is rapidly and completely bioactivated by ester hydrolysis to olmesartan during absorption from the gastrointestinal tract. Benicar tablets and the suspension formulation prepared from Benicar tablets are bioequivalent. The absolute bioavailability of olmesartan is approximately 26%. After oral administration, the peak plasma concentration (Cmax ) of olmesartan is reached after 1 to 2 hours. Food does not affect the bioavailability of olmesartan.
Total plasma clearance of olmesartan is 1.3 L/hr, with a renal clearance of 0.6 L/hr. Approximately 35% to 50% of the absorbed dose is recovered in urine while the remainder is eliminated in feces via the bile. ... Olmesartan shows linear pharmacokinetics following single oral doses of up to 320 mg and multiple oral doses of up to 80 mg. Steady-state levels of olmesartan are achieved within 3 to 5 days and no accumulation in plasma occurs with once-daily dosing.
Olmesartan is distributed into milk in rats; it is not known whether the drug is distributed into milk in humans.

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Metabolism / Metabolites
Olmesartan medoxomil is rapidly and completely bioactivated by ester hydrolysis to olmesartan during absorption from the gastrointestinal tract. This rapid first-pass metabolism was confirmed by the lack of measurable amounts of olmesartan medoxomil in plasma or excreta. This first-pass metabolism is not driven by cytochrome enzymes and hence it is not expected to interact with other drugs via this mechanism. The pharmacologically active moiety does not appear to undergo further metabolism.
Following the rapid and complete conversion of olmesartan medoxomil to olmesartan during absorption, there is virtually no further metabolism of olmesartan.

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Biological Half-Life
The mean plasma olmesartan half-life is reported to be from 10-15 hours after multiple oral administration.
Olmesartan appears to be eliminated in a biphasic manner with a terminal elimination half-life of approximately 13 hours.

Toxicity Summary
IDENTIFICATION AND USE: Olmesartan is a white to light yellowish-powder or crystalline powder that is formulated into oral tablets. Olmesartan is an angiotensin II type 1 (AT1) receptor antagonist. It is used alone or in combination with other classes of antihypertensive agents (e.g., thiazide diuretics) in the management of hypertension. HUMAN EXPOSURE AND TOXICITY: Limited data are available related to drug overdose in humans. The most likely manifestations of olmesartan overdose include hypotension and tachycardia; bradycardia could be encountered if parasympathetic (vagal) stimulation occurs. While olmesartan can be used in hypertensive children, it is not approved for use in children less one 1 year of age. Drugs that act directly on the renin-angiotensin system (RAS) can have effects on the development of immature kidneys. The use of olmesartan in pregnancy is also contraindicated. While use during the first trimester does not suggest a risk of major anomalies, use during the second and third trimester may cause teratogenicity and severe fetal and neonatal toxicity. Fetal toxic effects may include anuria, oligohydramnios, fetal hypocalvaria, intrauterine growth restriction, premature birth, and patent ductus arteriosus. Anuria-associated anhydramnios/oligohydramnios may produce fetal limb contractures, craniofacial deformation, and pulmonary hypoplasia. Severe anuria and hypotension, resistant to both pressor agents and volume expansion, may occur in the newborn following in utero exposure to olmesartan. ANIMAL STUDIES: Olmesartan was not carcinogenic when administered by dietary administration to rats for up to 2 years. Also, the fertility of male and female rats was unaffected by administration of olmesartan. No teratogenic effects were observed when drug was administered to pregnant rats at oral doses up to 1000 mg/kg/day or pregnant rabbits at oral doses up to 1 mg/kg/day. However, significant decreases in pup birth weight and weight gain were observed in rats. In addition, delays in developmental milestones (delayed separation of ear auricula, eruption of lower incisors, appearance of abdominal hair, descent of testes, and separation of eyelids) and dose-dependent increases in the incidence of dilation of the renal pelvis were observed in rats. Olmesartan tested negative in the in vitro Syrian hamster embryo cell transformation assay and showed no evidence of genetic toxicity in the Ames (bacterial mutagenicity) test. However, the drug was shown to induce chromosomal aberrations in cultured cells in vitro (Chinese hamster lung) and tested positive for thymidine kinase mutations in the in vitro mouse lymphoma assay. Olmesartan tested negative in vivo for mutations in the MutaMouse intestine and kidney and for clastogenicity in mouse bone marrow (micronucleus test) at oral doses of up to 2000 mg/kg.

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Hepatotoxicity
Olmesartan has been associated with a low rate of serum aminotransferase elevations (
Likelihood score: D (Possible rare cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
With the exception of one adverse reaction in a breastfed infant, no information is available on the use of olmesartan during breastfeeding. An alternate drug may be preferred, especially while nursing a newborn or preterm infant.
◉ Effects in Breastfed Infants
A 6-day-old healthy full-term newborn was exposed to olmesartan in breastmilk. The maternal dose of olmesartan and extent of nursing were not reported. Weight gain was normal during the first two weeks of life, but at the pediatric checkup on the 17th day postpartum, an abrupt decrease in body weight was recorded. He was hospitalized on the 21st day, and mixed feeding with milk and formula was started. Biochemical examinations showed aspartate-aminotransferase (AST) 250 mg/dL, and regular urinalysis. Virologic and metabolic causes of elevated transaminase were ruled out. The baby started to regain weight and his AST gradually normalized to 50 mg/dL by the 24th day. Olmesartan intake was stopped and the child was discharged on the 24th day of life.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Olmesartan is highly bound to plasma proteins. 99% of the administered dose is found in a bound state with no penetration in red blood cells.

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Interactions
Do not co-administer aliskiren with Benicar in patients with diabetes. Avoid use of aliskiren with Benicar in patients with renal impairment (GFR <60 mL/min).
Dual Blockade of the renin-angiotensin system (RAS)with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Most patients receiving the combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function and electrolytes in patients on Benicar and other agents that affect the RAS.
Increases in serum lithium concentrations and lithium toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists, including Benicar. Monitor serum lithium levels during concomitant use.
Potential pharmacologic interaction (attenuated hypotensive effects) when angiotensin II receptor antagonists are used concomitantly with nonsteroidal anti-inflammatory agents (NSAIAs), including selective cyclooxygenase-2 (COX-2) inhibitors. Possible deterioration of renal function, including possible acute renal failure, in geriatric, volume-depleted (including those receiving concomitant diuretic therapy), or renally impaired patients; renal function should be monitored periodically in patients receiving concomitant therapy with olmesartan and an NSAIA, including selective COX-2 inhibitors.
For more Interactions (Complete) data for Olmesartan (10 total), please visit the HSDB record page.

[1]. Effects of telmisartan and olmesartan on insulin sensitivity and renal function in spontaneously hypertensive rats fed a high fat diet. J Pharmacol Sci. 2016 Jul;131(3):190-7.

[2]. Olmesartan Inhibits Cardiac Hypertrophy in Mice Overexpressing Renin Independently of Blood Pressure: Its Beneficial Effects on ACE2/Ang(1-7)/Mas Axis and NADPH Oxidase Expression. J Cardiovasc Pharmacol. 2016 Jun;67(6):503-9.

[3]. Synergistic, cytotoxic and apoptotic activities of olmesartan with NF-κB inhibitor against HeLa human cell line. Toxicol Mech Methods. 2015;25(8):614-21.

Therapeutic Uses
Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents
Benicar is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including the class to which this drug principally belongs. There are no controlled trials demonstrating risk reduction with Benicar. Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program's Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC). Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly. Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment a lower blood pressure goal. Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy. It may be used alone or in combination with other antihypertensive agents. /Included in US product label/
Both angiotensin II receptor antagonists /including olmesartan/ and ACE inhibitors have been shown to slow the rate of progression of renal disease in hypertensive patients with diabetes mellitus and microalbuminuria or overt nephropathy, and use of a drug from either class is recommended in such patients. /NOT included in US product label/
Angiotensin II receptor antagonists /inlcuding olmesartan/ have been used with equivocal results in the management of congestive heart failure. While angiotensin II receptor antagonists appear to share the hemodynamic effects of ACE inhibitors, some clinicians state that in the absence of data documenting comparable long-term cardiovascular and/or renal benefits, angiotensin II receptor antagonists should be reserved principally for patients in whom ACE inhibitors are indicated but who are unable to tolerate the drugs (e.g., because of cough). /NOT included in US product label/
The antihypertensive effects of Benicar in the pediatric population were evaluated in a randomized, double-blind study involving 302 hypertensive patients aged 6 to 16 years. The study population consisted of an all black cohort of 112 patients and a mixed racial cohort of 190 patients, including 38 blacks. The etiology of the hypertension was predominantly essential hypertension (87% of the black cohort and 67% of the mixed cohort). Patients who weighed 20 to <35 kg were randomized to 2.5 or 20 mg of Benicar once daily and patients who weighed > or = 35 kg were randomized to 5 or 40 mg of Benicar once daily. At the end of 3 weeks, patients were re-randomized to continuing Benicar or to taking placebo for up to 2 weeks. During the initial dose-response phase, Benicar significantly reduced both systolic and diastolic blood pressure in a weight-adjusted dose-dependent manner. Overall, the two dose levels of Benicar (low and high) significantly reduced systolic blood pressure by 6.6 and 11.9 mm Hg from the baseline, respectively. These reductions in systolic blood pressure included both drug and placebo effect. During the randomized withdrawal to placebo phase, mean systolic blood pressure at trough was 3.2 mm Hg lower and mean diastolic blood pressure at trough was 2.8 mm Hg lower in patients continuing Benicar than in patients withdrawn to placebo. These differences were statistically different. As observed in adult populations, the blood pressure reductions were smaller in black patients. In the same study, 59 patients aged 1 to 5 years who weighed > or = 5 kg received 0.3 mg/kg of Benicar once daily for three weeks in an open label phase and then were randomized to receiving Benicar or placebo in a double-blind phase. At the end of the second week of withdrawal, the mean systolic/diastolic blood pressure at trough was 3/3 mm Hg lower in the group randomized to Benicar; this difference in blood pressure was not statistically significant (95% C.I. -2 to 7/-1 to 7).

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Drug Warnings
/BOXED WARNING/ WARNING: FETAL TOXICITY. When pregnancy is detected, discontinue Benicar as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.
Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Benicar as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus. In the unusual case that there is no appropriate alternative to therapy with drugs affecting the reninangiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Benicar, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.
Neonates with a history of in utero exposure to Benicar: If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.
FDA Pregnancy Risk Category: D /POSITIVE EVIDENCE OF RISK. Studies in humans, or investigational or post-marketing data, have demonstrated fetal risk. Nevertheless, potential benefits from the use of the drug may outweigh the potential risk. For example, the drug may be acceptable if needed in a life-threatening situation or serious disease for which safer drugs cannot be used or are ineffective./
For more Drug Warnings (Complete) data for Olmesartan (19 total), please visit the HSDB record page.

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Pharmacodynamics
Overall, olmesartan's physiologic effects lead to reduced blood pressure, lower aldosterone levels, reduced cardiac activity, and increased excretion of sodium. **Hypotension in Volume- or Salt-Depleted Patients** In patients with an activated renin-angiotensin aldosterone system, such as volume-and/or salt-depleted patients (e.g., those being treated with high doses of diuretics), symptomatic hypotension may be anticipated after initiation of treatment with olmesartan. Initiate treatment under close medical supervision. If hypotension does occur, place the patient in the supine position and, if necessary, give an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized. Valvular Stenosis: there is concern on theoretical grounds that patients with aortic stenosis might be at a particular risk of decreased coronary perfusion, because they do not develop as much afterload reduction. **Impaired Renal Function** As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals treated with olmesartan. In patients whose renal function may depend upon the activity of the renin-angiotensin- aldosterone system (e.g., patients with severe congestive heart failure), treatment with angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotemia and rarely with acute renal failure and/or death. Similar results may be anticipated in patients treated with olmesartan. In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen (BUN) have been reported. There has been no long-term use of olmesartan medoxomil in patients with unilateral or bilateral renal artery stenosis, but similar results may be expected. **Sprue-like Enteropathy** Severe, chronic diarrhea with substantial weight loss has been reported in patients taking olmesartan months to years after drug initiation. Intestinal biopsies of patients often demonstrated villous atrophy. If a patient develops these symptoms during treatment with olmesartan, exclude other etiologies. Consider discontinuation of olmesartan medoxomil in cases where no other etiology is identified. **Electrolyte Imbalances** Olmesartan medoxomil contains olmesartan, a drug that inhibits the renin-angiotensin system (RAS). Drugs that inhibit the RAS can cause hyperkalemia. Monitor serum electrolytes periodically.

C24H26N6O3

446.50

446.206

C, 64.56; H, 5.87; N, 18.82; O, 10.75

144689-24-7

Olmesartan-d4; 1420880-41-6; Olmesartan-d6; 1185144-74-4; Olmesartan medoxomil; 144689-63-4

158781

White to off-white solid powder

1.3±0.1 g/cm3

738.3±70.0 °C at 760 mmHg

186-188ºC

400.3±35.7 °C

0.0±2.6 mmHg at 25°C

1.671

3.72

3

7

8

33

656

0

O([H])C(C([H])([H])[H])(C([H])([H])[H])C1=C(C(=O)O[H])N(C([H])([H])C2C([H])=C([H])C(C3=C([H])C([H])=C([H])C([H])=C3C3N=NN([H])N=3)=C([H])C=2[H])C(C([H])([H])C([H])([H])C([H])([H])[H])=N1

VTRAEEWXHOVJFV-UHFFFAOYSA-N

InChI=1S/C24H26N6O3/c1-4-7-19-25-21(24(2,3)33)20(23(31)32)30(19)14-15-10-12-16(13-11-15)17-8-5-6-9-18(17)22-26-28-29-27-22/h5-6,8-13,33H,4,7,14H2,1-3H3,(H,31,32)(H,26,27,28,29)

5-(2-hydroxypropan-2-yl)-2-propyl-3-[[4-[2-(2H-tetrazol-5-yl)phenyl]phenyl]methyl]imidazole-4-carboxylic acid

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)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.60 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 25.0 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: ≥ 2.5 mg/mL (5.60 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 25.0 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: ≥ 2.5 mg/mL (5.60 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 25.0 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.)