Angiotensin II type 1 (AT1) receptor. [1]

Candesartan blocks the effects of angiotensin II at the angiotensin II type 1 (AT1) receptor. Candesartan cilexetil is a prodrug that is activated to candesartan by ester hydrolysis during gastrointestinal absorption.

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Candesartan improves the functional markers in a dose-dependent manner and also upregulates Ang (1-7), ACE2 and mas1 in the myocardium of DCM rats. Candesartan reduces various ER stress and apoptosis markers and the number apoptotic cells in the Candesartan treated rats. Candesartan cilexetil shows angiotensin-II blocking action in a dose-dependent manner in rats with dilated cardiomyopathy. Candesartan cilexetil reduces the left ventricular end-diastolic pressure and heart weight/body weight ratio, the area of myocardial fibrosis and expressions of transforming growth factor-beta1 and collagen-III mRNA. Candesartan cilexetil (1 mg/kg, p.o.) and enalapril (10 mg/kg, p.o.) reduces blood pressure to the same extent 5 hours after administration on the 1st and the 7th day. Candesartan cilexetil significantly increases renal blood flow without any changes in the cardiac index. TCV-116 and enalapril also tends to increase splanchnic blood flow following the 1st dose but not the 7th dose. Candesartan cilexetil is absorbed from the small intestine and hydrolyzed completely to the pharmacologically active metabolite M-I during absorption process.
In hypertensive patients (sitting DBP 95-114 mmHg), Candesartan cilexetil produced dose-dependent reductions in blood pressure at dosages of 2-32 mg/day. A meta-analysis of six randomized trials (1482 patients) showed placebo-corrected reductions in sitting DBP: 2.5 mmHg for 2 mg, and higher for 4-16 mg (statistically significant). Response rates ranged from 35% (2 mg) to 55% (16 mg) vs placebo 20-28%. [1]
In a double-blind dose-ranging trial (Reif et al., n=332), Candesartan cilexetil 2-32 mg/day for 8 weeks significantly decreased mean sitting DBP by 7.1-10.2 mmHg vs placebo 2.6 mmHg (p<0.005). Response rates: placebo 20%, 16 mg 54%, 32 mg 64%. Reductions noted within 2 weeks. Another dose-ranging trial (Bell et al.) found 32 mg/day more effective than 16 mg, which was more effective than 8 mg; 64 mg/day gave no additional benefit. [1]
Ambulatory blood pressure monitoring (238 patients, 12 weeks) showed significant reductions in mean ambulatory DBP throughout the day for Candesartan cilexetil 4-16 mg/day vs placebo (p<0.001), with trough-to-peak ratio of 0.8 supporting once-daily regimen. [1]
Comparative trial vs enalapril (Franke, 364 patients, 12 weeks): Candesartan cilexetil 8 or 12 mg/day and enalapril 10 mg/day produced similar reductions in sitting DBP (10.5±9.9, 10.0±10.0, 10.6±9.8 mmHg respectively) vs placebo (p<0.01). Response rates: candesartan 4 mg 53.0%, 8 mg 69.1%, enalapril 69.0%, placebo 41.5%. [1]
Another comparative trial (Zanchetti et al., 205 patients, 8 weeks, dose-titration): Candesartan cilexetil 4-8 mg/day and enalapril 10-20 mg/day produced similar reductions in sitting DBP (10.1±6.6 and 10.5±6.6 mmHg respectively, p<0.001 vs placebo). 36.7% of candesartan patients required dose doubling. [1]
Comparison vs losartan (337 patients, 8 weeks): Candesartan cilexetil 8 mg reduced mean sitting DBP by 8.9 mmHg; 16 mg reduced by 10.3 mmHg, significantly more effective than losartan 50 mg (mean between-group difference 3.7 mmHg, p=0.013). [1]
Combination with hydrochlorothiazide (HCTZ): In a French trial (n=234), adding Candesartan cilexetil 4 or 8 mg to HCTZ 12.5 mg/day significantly reduced sitting DBP (7.0±8.0 and 7.9±9.6 mmHg respectively, p<0.05 vs placebo+HCTZ). Response rates 47% and 54% vs 33% for placebo+HCTZ. [1]
Another combination trial (n=1096, 15 groups, 8 weeks): Candesartan cilexetil 2-16 mg with HCTZ 12.5 or 25 mg showed dose-dependent reductions. Largest reduction in sitting DBP (16.6 mmHg) with candesartan 16 mg + HCTZ 12.5 mg (p<0.01 vs monotherapy), response rate 85%. [1]
In African-American patients with severe hypertension (sitting DBP ≥110 mmHg, n=209), Candesartan cilexetil 8-16 mg/day added to HCTZ 12.5 mg reduced mean sitting DBP by 8.6 mmHg vs 1.9 mmHg for placebo+HCTZ (p=0.0035) after 4 weeks. [1]
Comparison with amlodipine (abstract): Candesartan cilexetil 8-16 mg/day is as effective as amlodipine 5 mg/day; combination produced greater reductions. [1]
In hypertensive patients with type 2 diabetes and albuminuria (n=161, 12 weeks), Candesartan cilexetil 8-12 mg/day decreased urinary albumin excretion compared to placebo (p=0.03). [1]
In congestive heart failure (RESOLVD trial, n=768, 43 weeks, terminated early): Candesartan cilexetil 4-16 mg/day had mortality rate 6.1% (vs enalapril 3.7%, combination 8.7%). Combination with enalapril prevented progression of left ventricular dilation and neurohormonal activation (smaller increases in left ventricular volume, greater decreases in aldosterone). No significant difference in 6-minute walking distance or quality of life. [1]

1 mg/kg, p.o.

Rats

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Absorption, Distribution and Excretion
Following administration of the candesartan cilexetil prodrug, the absolute bioavailability of candesartan cilexetil is estimated to be 15%. High-fat diets have no effect on the bioavailability of candesartan cilexetil. Approximately 26% of the oral dose of candesartan cilexetil is excreted unchanged in the urine. Candesartan is primarily excreted unchanged in the urine and feces (via bile). 0.13 L/kg 0.37 mL/min/kg hr Metabolism/Metabolites The prodrug candesartan cilexetil is rapidly and completely esterified in the intestinal wall to produce the active drug, candesartan. Candesartan is primarily excreted unchanged in the urine and via the bile route in the feces. A small amount of hepatic metabolism of candesartan (<20%) occurs via O-deethylation at cytochrome P450 2C9, producing an inactive metabolite. Candesartan undergoes N-glucuronidation of the tetrazolium ring via uridine diphosphate glucuronyl transferase 1A3 (UGT1A3). O-glucuronidation may also occur. 75% of candesartan is excreted unchanged in urine and feces.

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Biological half-life
Approximately 9 hours.

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Candesartan cilexetil is a prodrug activated to candesartan by ester hydrolysis during gastrointestinal absorption. In healthy volunteers, after oral administration of 8 mg, absorption was rapid with absolute bioavailability of 42% (range 34-56%). The terminal half-life (t1/2) was approximately 9 hours (range 6.6-16.0 hours). Time to maximum concentration (tmax) was 1.25 hours (range 0.46 hours). Maximum serum concentration (Cmax) was 229 ng/mL (range 179-298 ng/mL). Area under the curve (AUC) was 1390 ng·hr/mL (range 1140-1610 ng·hr/mL). Volume of distribution (V) was 0.13 L/kg (range 0.09-0.17 L/kg). Clearance (CL) was 0.37 mL/min/kg (range 0.31-0.47 mL/min/kg). [1]
In elderly patients (65-78 years), t1/2 was slightly longer (9-12 hours) and tmax occurred at 7-9 hours. Linear relationships between dose and AUC/Cmax were observed in both young and elderly. [1]
Candesartan cilexetil is largely eliminated unchanged through biliary excretion. It is minimally metabolized via cytochrome P-450 isoenzyme 2C9 to an inactive metabolite (CV 15959). Serum levels of CV 15959 were much lower than candesartan, peaking at 4-9 hours. [1]
After intravenous administration of 4 mg candesartan cilexetil, Cmax was 984 ng/mL (788-1300 ng/mL) at 12 minutes, V 0.13 L/kg, CL 0.37 mL/min/kg, t1/2 9.7 hours. Most radioactivity (52.3% for IV, 25.7% for oral) excreted in urine and feces as candesartan within first 72 hours. [1]
Food does not affect bioavailability: AUC (642 vs 636 ng·hr/mL), t1/2 (9.1 vs 9.4 hours), and CL (10.9 vs 10.7 mL/min) were similar after fatty meal vs fasting. [1]
In patients with mild to moderate hepatic impairment, no significant differences in pharmacokinetic parameters after single or multiple doses of 12 mg/day; no accumulation. Studies not performed in severe hepatic dysfunction. No initial dosage adjustment needed for mild hepatic disease. [1]
In renal impairment (mild to severe), AUC, Cmax, and t1/2 were increased. In patients with severe renal impairment (CLcr 15-30 mL/min/1.73m²) or on hemodialysis, mean DBP reduction was 12.5 mmHg vs 10.8 mmHg for mild-moderate and 17 mmHg for normal renal function after multiple daily doses of 12 mg/day. Accumulation occurred at 8 mg/day in hemodialysis patients (greater than severe impairment) but without adverse effect on BP response. Candesartan cilexetil was not appreciably removed by hemodialysis (mean extraction ratio 0.18). [1]
In patients with renal artery stenosis, dehydration, or CHF (where efferent arterial tone depends on angiotensin II), ARBs like candesartan have less impact on renal hemodynamics than ACE inhibitors, with only infrequent increases in BUN and creatinine. [1]

Protein Binding
Candesartan has a high binding rate to plasma proteins (>99%) and cannot penetrate red blood cells.

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Adverse effects reported in clinical trials were mild to moderate and included headache, lightheadedness, dizziness, nausea, diarrhea, and transient elevations in serum liver transaminases. Frequency of cough was similar to placebo (<3%) and lower than lisinopril (23.9%). No substantial changes in heart rate or orthostatic blood pressure. [1]
When combined with hydrochlorothiazide, the proportion of adverse effects increased but no specific event increased in frequency. [1]
No significant disturbances in potassium homeostasis; no effect on glucose, hemoglobin A1c, or lipid profile in hypertensive patients with type 2 diabetes. [1]
Long-term studies (6-12 months, n=632) showed adverse events occurred within first 3 months of therapy and then declined. No relationship between adverse effects and dosage, race, or age. [1]
Given the risk of fetal injury and death associated with agents acting on the RAAS during the second and third trimesters, Candesartan cilexetil should be discontinued if pregnancy is detected. [1]

Am J Health Syst Pharm.2000 Apr 15;57(8):739-46;Toxicology.2012 Jan 27;291(1-3):139-45.

Candesartan medoxomil belongs to the biphenyl class of compounds. Candesartan is an angiotensin receptor blocker (ARB) that can be used alone or in combination with other drugs to treat hypertension. It is taken orally as a prodrug, candesartan medoxomil, and is rapidly converted to its active metabolite, candesartan, during gastrointestinal absorption. Candesartan lowers blood pressure by antagonizing the renin-angiotensin-aldosterone system (RAAS); it competitively binds to the type 1 angiotensin II receptor (AT1) subtype with angiotensin II, thereby blocking the pressor effect of angiotensin II. Unlike angiotensin-converting enzyme (ACE) inhibitors, ARBs do not cause adverse reactions such as dry cough. Candesartan can be used to treat hypertension, isolated systolic hypertension, left ventricular hypertrophy, and diabetic nephropathy. It can also be used as an alternative treatment for heart failure, systolic dysfunction, myocardial infarction, and coronary artery disease. Candesartan medoxomil is a synthetic benzimidazole angiotensin II receptor antagonist prodrug with antihypertensive activity. Candesartan medoxomil is hydrolyzed to candesartan during gastrointestinal absorption. It selectively competes with angiotensin II for binding to angiotensin II receptor type 1 (AT1) in vascular smooth muscle, thereby blocking angiotensin II-mediated vasoconstriction and inducing vasodilation. Furthermore, antagonism of AT1 in the adrenal glands inhibits angiotensin II-stimulated aldosterone synthesis and secretion from the adrenal cortex; sodium and water excretion increases, followed by a decrease in plasma volume and blood pressure. See also: candesartan (containing the active ingredient); candesartan medoxomil; hydrochlorothiazide (one of the components). Drug Indications Candesartan can be used as a first-line drug for the treatment of isolated hypertension, isolated systolic hypertension, and left ventricular hypertrophy. It can also be used as a first-line drug to slow the progression of diabetic nephropathy. Candesartan can also be used as a second-line drug for the treatment of patients with congestive heart failure, systolic dysfunction, myocardial infarction, and coronary artery disease who are intolerant to ACE inhibitors.
FDA Label
Diabetic Retinopathy, Essential Hypertension, Heart Failure
Diabetic Retinopathy, Essential Hypertension, Heart Failure
Mechanism of Action

Candesartan selectively blocks the binding of angiotensin II to AT1 receptors, acting on multiple tissues including vascular smooth muscle and the adrenal glands. This inhibits the vasoconstriction and aldosterone secretion mediated by angiotensin II via AT1 receptors, resulting in an overall decrease in blood pressure. Candesartan is more than 10,000 times more selective for AT1 receptors than for AT2 receptors. Inhibition of aldosterone secretion increases sodium and water excretion while decreasing potassium excretion.
Pharmacodynamics

Candesartan cilexetil is an angiotensin receptor blocker (ARB) prodrug that is rapidly converted to its active metabolite, candesartan, during gastrointestinal absorption. Candesartan exerts its antihypertensive effect by antagonizing the pressor effect of angiotensin II, thereby acting through the renin-angiotensin-aldosterone system (RAAS). The renal juvenile autoimmune system (RAAS) is a homeostatic mechanism regulating hemodynamics, water, and electrolyte balance. When the sympathetic nervous system is excited or renal blood pressure or blood flow decreases, the granular cells of the juxtaglomerular apparatus release renin. Renin cleaves circulating angiotensinogen into angiotensin I, which is then cleaved into angiotensin II by angiotensin-converting enzyme (ACE). Angiotensin II raises blood pressure by increasing peripheral resistance, promoting aldosterone secretion, increasing renal reabsorption of sodium and water, and altering cardiovascular structure. Angiotensin II binds to two receptors: angiotensin II receptor type 1 (AT1) and angiotensin II receptor type 2 (AT2). AT1 is a G protein-coupled receptor (GPCR) that mediates the vasoconstrictive and aldosterone secretion effects of angiotensin II. Recent studies have shown that AT2 antagonizes the effects mediated by AT1 and directly affects long-term blood pressure control by inducing vasodilation and increasing urinary sodium excretion. Angiotensin receptor blockers (ARBs) are non-peptide competitive inhibitors of AT1. ARBs block the vasopressive and cell proliferation-stimulating effects of angiotensin II. Unlike ACE inhibitors, ARBs do not affect bradykinin-induced vasodilation. The overall effect of ARBs is to lower blood pressure.

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Candesartan cilexetil is indicated for the treatment of hypertension, either as monotherapy or in combination with other antihypertensive agents. [1]
Unlike ACE inhibitors, ARBs (including candesartan) do not inhibit ACE and have no effect on bradykinin, thus avoiding ACE inhibitor-related cough and angioedema. ARBs provide complete blockade of angiotensin II from both ACE-dependent and non-ACE-dependent pathways (e.g., chymase), overcoming "angiotensin escape" seen with ACE inhibitors. [1]
In the RESOLVD pilot study, the combination of enalapril and Candesartan cilexetil helped prevent progression of left ventricular dilation and neurohormonal activation, but a trend toward increased mortality was noted in the combination group (8.7% vs 6.1% for candesartan alone and 3.7% for enalapril alone). Further studies are needed. [1]
No clinically important drug interactions were reported with nifedipine, glyburide, digoxin, oral contraceptives, or warfarin (no effect on prothrombin time). Hydrochlorothiazide 25 mg increased bioavailability of candesartan by 20% but no hypotensive effect reported in healthy volunteers; however, enhanced BP reductions seen in hypertensive patients. [1]
Patients should be informed that a blood pressure response may occur as early as two weeks, with maximum reduction after four to six weeks. Candesartan cilexetil may be taken without regard to food. [1]

C33H34N6O6

610.66

610.253

145040-37-5

Candesartan;139481-59-7;Candesartan-d4;1346604-70-3

2540

White to off-white solid powder

1.4±0.1 g/cm3

843.3±75.0 °C at 760 mmHg

168-170?C

463.8±37.1 °C

0.0±3.1 mmHg at 25°C

1.667

7.79

1

10

13

45

962

0

GHOSNRCGJFBJIB-UHFFFAOYSA-N

InChI=1S/C33H34N6O6/c1-3-42-32-34-28-15-9-14-27(31(40)43-21(2)44-33(41)45-24-10-5-4-6-11-24)29(28)39(32)20-22-16-18-23(19-17-22)25-12-7-8-13-26(25)30-35-37-38-36-30/h7-9,12-19,21,24H,3-6,10-11,20H2,1-2H3,(H,35,36,37,38)

1-(((cyclohexyloxy)carbonyl)oxy)ethyl 1-((2-(1H-tetrazol-5-yl)-[1,1-biphenyl]-4-yl)methyl)-2-ethoxy-1H-benzo[d]imidazole-7-carboxylate

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 (4.09 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 (4.09 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.)