Candesartan cilexetil

Uses

1. Candesartan cilexetil(145040-37-5) is a prodrug of the potent, long-acting, and selective angiotensin II type 1 receptor AT1 antagonist, candesartan. It is rapidly hydrolyzed to candesartan during gastrointestinal absorption. After hydrolysis of candesartan cilexetil to candesartan during gastrointestinal absorption, candesartan selectively competes with angiotensin II for the binding of the angiotensin II receptor subtype 1 AT1 in vascular smooth muscle, blocking angiotensin II-mediated vasoconstriction and inducing vasodilatation. In addition, antagonism of AT1 in the adrenal gland inhibits angiotensin II-stimulated aldosterone synthesis and secretion by the adrenal cortex; sodium and water excretion increase, followed by a reduction in plasma volume and blood pressure.
2. Candesartan cilexetil can be used as pesticide and pharmaceutical intermediates.
3. It can be used as the raw material of antihypertensive drugs.
4. Candesartan is an angiotensin-receptor blocker (ARB)，Angiotensin receptor blockers effectively protect against the harmful effects of the activation of the renin-angiotensin-aldosterone system that occur with hypertension or diabetes.It may be used alone or with other agents to treat hypertension. Unlike angiotensin-converting enzyme (ACE) inhibitors, ARBs do not have the adverse effect of dry cough.
5. Candesartan may be used to treat hypertension, isolated systolic hypertension, left ventricular hypertrophy and diabetic nephropathy. It may also be used as an alternative agent for the treatment of heart failure, systolic dysfunction, myocardial infarction and coronary artery disease.

The precursor drug of Antihypertensive drug Candesartan---Candesartan cilexetil

Hypertension disease, due to its high incidence, high morbidity and high mortality as well as the resulted various kinds of issues including medical, social, family, economic, has changed from purely personal disease to serious social issues. Study and development of first-line drug treatment of hypertension has increasingly become the focus of the world's major competing focus of many major manufacturers. The main purpose of the treatment of hypertension is to minimize the total risk of cardiovascular disease death and disability with its goal being able to restore blood pressure to 140/90mmHg or less.
Currently, there are many kinds of clinical anti-hypertensive drugs and can be primarily divided into five categories, namely, diuretics, β-blockers, angiotensin-converting enzyme inhibitors (ACE-Ⅰ), calcium antagonists, and α-blockers. They all have certain limitations and side effects in use. Since the 1980s, ACE-I have been widely used to treat a variety of cardiovascular diseases and have been demonstrated to have excellent pressure-lowering effect on high blood pressure. However, since the ACE-Ⅰ also inhibits the degradation of bradykinin, and thus often resulting dry cough during the treatment of patients.
Currently, a new class of anti-hypertensive drugs-angiotensin Ⅱ receptor antagonist has been listed. A typical representative of such drugs includes losatran (Merck), valsartan (Novartis) and eprosartan (SmithKline). As the role of these drugs are more specific than the ACE-I, increasing the antihypertensive effect with reduced side effects as well as not causing cough. It also has protective effects on blood vessels, kidneys and heart. Therefore, this type of drug has become a competition protagonist in the hypertension drug market.
Candesartan cilexetil is the pro-drug of candesartan with the action strength being 10 times as high as losatran. Its action has a good selectivity (has a 10000 time higher affinity to AT1 receptor than AT2), long duration of action (take it one time daily). As a pro-drug, it can release its activity in a relatively mild way after oral administration, making it be a kind of ideal drug for treatment of hypertension.
According to the foreign prediction, the annual sales of this kind of goods can reach up to $ 2 billion so the development of this product will surely achieve good economic and social benefits.

Candesartan cilexetil tablets

[Appearance] it is white or white-like drug.
[Pharmacological and toxicological effects] Candesartan cilexetil is rapidly hydrolyzed in vivo to become active metabolite-----candesartan. Candesartan is a selective angiotensin Ⅱ receptor (AT1) antagonist and can antagonize the with the vasoconstriction effect of angiotensin II through binding to the vascular smooth muscle AT1 receptor, thereby reducing peripheral vascular resistance. Others also suggest that: candesartan can suppress the adrenal secretion of aldosterone and thus playing a role of lowering the blood pressure. Candesartan neither inhibits kininase Ⅱ nor affects bradykinin degradation. Experiments of hypertensive patients have demonstrated that: multi-administration of this drug by the patients can cause increase of the plasma renin activity, angiotensin I concentration and angiotensin Ⅱ concentration; taking this drug continuously for 2-8 mg per day can reduce the systolic blood pressure, diastolic blood pressure, left ventricular mass, as well as peripheral vascular resistance while having no significant effect on cardiac output, ejection fraction, renal vascular resistance, renal blood flow, glomerular filtration rate; It also has no significant effect on the cerebral blood flow of patients of original sexual hypertensive patients with cerebral vascular disorder. Toxicological studies: mice, rats and dogs with oral administration of 2000 mg/kg candesartan cilexetil once have no deaths. The maximal tolerated dose of this drug of the NIH mice through oral administration can reach up to 6750mg/kg. The non-toxic dose of long-term (26 weeks) oral administration of this drug by rats is 10mg/kg.d. The non-toxic dose for beagle dogs being subject to long-term oral administration of this drug is 20mg/kg. d. Tests on mutagenic, carcinogenic, reproductive harm have demonstrated that candesartan cilexetil has no mutagenic effects in separation tests including microbial mutation, chromosomal aberrations and gene mutations in mammalian DNA. When rats and mice were given the product of 300 and 1000 mg/kg for continuous 2 years (104 weeks) showed no carcinogenic effect (this dose was 7 fold and 70 fold of the recommended human daily maximum dose of 32mg/d, respectively). When male and female rats were fed 300 mg/kg.d of this drug (83 fold of the maximum recommended human dose), no effect on fertility and fecundity has been observed. Reproductive and embryo toxicity test has showed: oral administration by rats during late pregnancy and lactation in a dose of 10mg/kg. d can reduce the number of viable offspring as well as cause rising incidence of hydronephrosis (2.8 fold of the maximum recommended human dose). Oral administration of this drug by pregnant rabbits in a dose of 3mg/kg/d (approximately 1.7 fold of the maximum recommended human dose) can cause maternal toxicity (weight loss or death), but have no negative effects on the survival rate of the maternal fetal, weight, shape, visceral and skeletal development. Oral administration of this drug by pregnant until 1000mg/kg/d (approximately 138 fold of the maximum recommended human dose) cause no maternal toxicity and any adverse effects on fetal development.

Appendix I

[Pharmacokinetics] candesartan cilexetil is the pro-drug of candesartan. It is rapidly and totally hydrolyzed into candesartan during the absorption in gastrointestinal tract. The absolute bioavailability of candesartan is about 15%. The time for candesartan plasma concentration to reach peak is 3 to 4 hours. Candesartan has a plasma protein binding rate of being greater than 99% with the apparent volume of distribution of 0.13L/kg. Rat tests have shown that candesartan rarely penetrates through blood-brain barrier but can penetrate through the placental barrier and be distributed in fetal. Candesartan is mainly excreted in its prototype from the urine and feces with a very small part in the liver being metabolized into inactive metabolites through O-Alkylation reaction. The excretion half life of candesartan is about 9 hours. Data have shown that candesartan total clearance rate was 0.37mL/min. kg, renal clearance rate of 0.19mL/min.kg. After oral administration of 14C-labeled candesartan cilexetil, about 33% and 67% of the radioactivity were recovered from urine and feces, respectively. Special Populations Elderly and gender: The pharmacokinetics parameters analysis about the product used in 65 years of age or older and different genders have shown that: upon the same drug dose, older group has a higher plasma concentration than youth group while there is no significant difference between men and women. For patients of liver, renal insufficiency and patients with severe hepatic, renal insufficiency, it is necessary to adjust the initial dose.
[Indications] it can be used for the treatment of essential hypertension. It can be used alone or with combined with other antihypertensive drugs.
[Usage and dosage] Oral, generally take once per day for adult 1, 1 4~8 mg per time; increase the dose to 12 mg if necessary.
[Pediatric Use] The safety of children's medication has not been determined (no experience).
[Treatment of elderly patients] it is generally believed that the elderly should not be treated with excessively lowering blood pressure (may cause cerebral infarction, etc.). Patients should be treated cautiously during the observation of their state. For elderly people with normal liver and kidney function, use an initial dose of 4mg; for those with renal insufficiency or liver function, it is recommended that the initial dose of 2mg; the dose should be increased or decreased according to the actual status of the disease.
The above information is edited by the Chemicalbook of Dai Xiongfeng.

Appendix II

[Medication of pregnant women and lactating women] upon the administration of this preparation for perinatal and lactating rats, you can see that, for groups with more than 10mg/kg/day dose, there is increase in the incidence of newborn hydronephrosis, it has also been reported that during middle and late pregnancy, for hypertension patients of administration of angiotensin II receptor antagonists (including candesartan) or angiotensin-converting enzyme inhibitors, there were many kinds of adverse reactions including oligohydramnios disease, fetal, neonatal death, neonatal hypotension, renal failure, hyperkalemia, skull hypoplasia, and may also limb contractures, craniofacial malformations due to too little amniotic fluid. Pregnant or possible pregnant women should be banned for using the drug. In addition only when administration of this drug at late pregnancy or lactating rats at 300mg/kg/day dose group will the newborn hydronephrosis increase. Lactating women should avoid medication and stop breastfeeding when necessary medication is inevitable.
[Drug interactions] pay attention to combination (concomitant medication should be paid attention to). This good has no obvious interaction with glyburide, nimodipine, digoxin, warfarin, and hydrochlorothiazide and other drugs. In the case of healthy people with simultaneous oral administration of contraceptives, no significant interactions have been found.
[Overdosage] According to pharmacological studies, the main behavior of overdose is symptomatic hypotension and dizziness. If symptomatic hypotension occurs, symptomatic treatment must be conducted and some important living signs should be monitored. Patients should be place in the supine with low head and high feet. The patient should also be subject to isotonic saline injection to increase his/her plasma volume if necessary. If the above measures still don’t work, the patients can be subject to the treatment of sympathomimetic drugs.
[Storage] stored after being sealed and dried.
[Prescription or not]: prescription

Side effects and adverse reactions

Serious adverse effects (incidence unknown) :
1, angioedema: sometimes neovascularization edema located in face, lips, tongue, pharynx, and larynx; this should be carefully observed and stop medication upon abnormal cases with taking further appropriate treatment.
2, Syncope and loss of consciousness: excessively lowing blood pressure may cause temporary loss of consciousness and fainting. In this case, the medication should be stopped and the patients should be subject to appropriate treatment. Especially for patients undergoing hemodialysis, patients undergoing strict salt restriction therapy as well as patient who have recently started taking diuretic antihypertensive drugs, rapid reduction of blood pressure can occur. Therefore, these patients using this drug should start from a lower dose. If it is necessary to increase the dose, the patient should be closely observed the situation and slowly increases the dose.
3, Acute renal failure: acute renal failure can occur; we should closely observe the patient's condition and the medication should be stopped upon unusual cases with further taking appropriate treatment.
4, Patients with hyperkalemia: Given that hyperkalemia may occur, the patient should be closely observed for their conditions. If abnormal conditions happen, the patients should stop medication and be subject to appropriate treatment.
5, Deterioration of liver function or jaundice: since there may be liver dysfunction or jaundice with AST (GOT), ACT (GPTO, γ-GTP) value being elevated; If abnormal conditions happen, the patients should stop medication and be subject to appropriate treatment.
6, Agranulocytosis: there may be agranulocytosis occurring, the patient should be closely observed for their conditions. If abnormal conditions happen, the patients should stop medication and be subject to appropriate treatment.
7, Rhabdomyolysis: it may be manifested as muscle pain, weakness, CK increase and myosin showing in blood and urine. When that happens, the patients should stop medication and be subject to appropriate treatment.
8, Interstitial pneumonia: it may occur with fever, cough, difficulty breathing, and chest X-ray abnormalities. When these above conditions occur, the patients should stop medication and be subject to appropriate treatment such as adrenal corticosteroids.
[Taboo]
1, Patients who have allergic history on the components of this formulation.
2, pregnant or possibly pregnant women (refer to the part of [pregnant women and lactating women drug]).
3, Patients of severe liver, renal insufficiency or patients with cholestasis.

Precautions

1, Use it with caution (following patients should use caution)
(1) Patient of bilateral or unilateral renal artery (see important basic precautions in 2).
(2) There is hyperkalemia in patients (see important basic precautions in part 2).
(3) Patients with liver dysfunction (possible deterioration of liver function. And, this is presumably the reduced clearance rate of the active metabolite candesartan occurring and therefore the patients should start from small dose and take medication with caution, refer to [Pharmacokinetics] item).
(4) Patients of renal dysfunction (due to excessively lowered blood pressure, it has the potential to worsen renal function, so once per day and start taking careful medication from 2 mg).
(5) Patients with a history of drug allergy.
(6) Elderly patients (see item [elderly patients]).
(7) Renal transplantation: For patients who have been recently subject to kidney transplant, there is still no experience of using this drug product.
(8) Patients of aorta and the left atrioventricular valve stenosis (obstructive hypertrophic cardiomyopathy disease): Patients using other vasodilators, patients with hemodynamic-related artery or left atrioventricular valve stenosis or obstructive hypertrophic cardiomyopathy should particularly take with caution.
(9) Patients with mild to moderate adrenal hyperandrogenism: patients with mild to moderate adrenal hyperandrogenism usually don't respond to antihypertensive drugs which suppress the renin-angiotensin-aldosterone system. Therefore, it is not recommended to use this drug.
2, Some important basic precautions
(1) for patients of bilateral or unilateral renal artery stenosis, upon taking renin-angiotensin-aldosterone system drugs, due to the reduction of renal blood flow and reduction of the filtration pressure, it can increase the risk of kidney function; Unless the treatment is necessary, the patients should avoid taking the drug.
(2) Since it may aggravate hyperkalemia, unless treatment is considered to be essential, patients with hyperkalemia should avoid taking the drug. In addition, patients of renal dysfunction, uncontrolled diabetes should be closely monitored about their serum potassium level as these patients tend to develop hyperkalemia
(3) Since upon taking this preparation, sometimes there may be a sharp decline in blood pressure, especially for the following patients, it should start from small dose and when increase the dose, we should carefully observe the condition of the patient and conduct slowly. A, patients undergoing hemodialysis; B, Patients undergoing strict salt restriction therapy; C, Patients taking diuretic antihypertensive drugs (particularly patients who have recently started taking diuretic antihypertensive drugs).
(4) Because of the antihypertensive effect, it can sometimes cause dizziness, staggering; thus upon high-altitude operations, we should pay attention to driving and other operations.
(5) It is better to stop taking it at 24 hours before surgery
(6) For the drug delivery: drug of PTP packaging should be taken after being moved out from PTP sheet (it has been reported that the mistakenly oral intake PTP sheet penetrate the hard acute esophageal mucosa, thereby causing perforation, and mediastinitis).

References

https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/020838s022lbl.pdf
http://www.rxlist.com/atacand-drug.htm

Description

Candesartan cilexetil is a prodrug form of the angiotensin II type 1 receptor (AT1) antagonist candesartan . Atacand was launched in Australia, Belgium, Canada, Denmark, Finland, the Netherlands, Norway, Sweden, S. Africa and the US as an antihypertensive agent. Pharmacological studies have indicated Atacand is about 10-fold more potent than Losartan and has a long elimination half-life. Like losartan, Atacand is converted to its active form during GI absorption (via ester hydrolysis). It is a potent antagonist of angiotensin II type 1 receptors. This occurs through tight binding and slow dissociation, and is more potent than ACE inhibitors. It is well tolerated (can be taken by elderly and those with type II diabetes) and has no gender effects.

Chemical Properties

It appears as a white or off-white powder.It is soluble in methanol but insoluble in water.

Originator

Takeda (Japan)

Uses

N,N-Desmethoxyethyl Candesartan Cilexetil is an impurity of Candesartan Cilexetil(C175580); An antihypertensive used in the treatment of congestive heart failures.

Definition

ChEBI: Candesartan cilexetil is a member of biphenyls.

Manufacturing Process

3-Nitrophthalic acid (35 g) in 300 ml ethanol and 20 ml concentrated sulfuric acid was heated under reflux for 24 hours. The solvent was evaporated in vacuo and the residue was poured into 700 ml cold water. The mixture was extracted with ethyl acetate. The aqueous layer was made acidic with hydrochloric acid and the mixture was extracted with methylene chloride. After evaporation of methylene chloride was obtained 29 g (74%) ethyl 2- carboxy-3-nitrobenzoate.
A mixture of 23.9 g ethyl 2-carboxy-3-nitrobenzoate and 12 ml thionyl chloride in 150 ml benzene were heated under reflux for 3 hours. The reaction mixture was concentrated to dryness. The resultant acid chloride (26 g) was dissolved in 20 ml. The solution was added to a mixture of sodium azide (9.75 g) in 20 ml DMF with stirring. The reaction mixture was poured into 200 ml a mixture of ether-hexane (3:1). The organic layer was washed with water and evaporated. The residue was dissolved in 200 ml tert-butanol and the solution was heated gradually with stirring, followed by heating under reflux for 2 hours. The reaction mixture was concentrated to give an oily ethyl 2- butoxycarbonylamino-3-nitrobenzoate (30 g).
To a solution of ethyl 2-butoxycarbonylamino-3-nitrobenzoate (29 g) in 50 ml THF was added, while stirring under ice-cooling, sodium hydride (60% dispersion in mineral oil, 2.8 g). After 20 min to the mixture were added 18 g 4-(2-cyanophenyl)benzyl bromide and 0.36 g potassium iodide. After heating for 10 hours under reflux the solvent was evaporated and the residue was partitioned between 250 ml water and 200 ml ether. The organic layer was washed with water, dried and concentrated to give yellow syrup. The syrup was dissolved in a mixture of 60 ml trifluoroacetic acid and 40 ml methylene chloride and the solution was stirred for 2 hour at room temperature. The reaction mixture was concentrated to dryness and to residue was added 200 ml ethyl ether to give crystals of ethyl 2-[(2'-cyanobiphenyl-4- yl)methylamino]nitrobenzoate (22.1 g, 85%), M.P. 118-119°C.
To a solution of 10.4 g ethyl 2-[(2'-cyanobiphenyl-4-yl)methylamino] nitrobenzoate in 50 ml ethanol was added 28.1 g stannous dichloride dihydrate and the mixture was stirred for 2 hours at 80°C. The solvent was evaporated. To the ice-cooling mixture of the residue in 300 ml ethyl acetate was added dropwise 2 N NaOH (500 ml). The aqueous layer was extracted with ethyl acetate (200 ml x 2). The organic layers were combined and evaporated to dryness. Product was purified by column chromatography on silica gel. Recrystallization from ethyl acetate-hexane gave colorless crystals ethyl-3-amino-2-[[(2'-cyanobiphenyl-4-yl)methyl]amino]benzoate (7.3 g, 79%), M.P. 104-105°C.
Acetic acid (0.2 g) was added to a solution of ethyl-3-amino-2-[[(2'- cyanobiphenyl-4-yl)methyl]amino]benzoate (1 g) in ethylorthocarbonate (5 ml). The mixture was stirred at 80°C for 1 hours. The reaction mixture was concentrated. The solution was washed with an aqueous solution of NaHCO3 and water. The solvent was evaporeted to give crystals. Recrystallization from ethyl acetate-benzene afforded colorless crystals 1-[(2'-cyanobiphenyl-4- yl)methyl]-2-ethoxybenzimidazole-7-carboxylate (0.79 g, 69%), M.P. 131- 132°C.
A mixture of 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-ethoxybenzimidazole-7- carboxylate (0.7 g) and trimethyltin azide (0.7 g) in toluene (15 ml) was heated under reflux for 4 days. The reaction mixture was concentrated, and to the residue were added methanol (20 ml) and 1 N HCl (10 ml). The solution was stirred at room temperature for 30 minutes and adjusted to pH 3-4 with 1 N NaOH. After removal of the solvent, the residue was partitioned between chloroform and water. The organic layer was evaporated to dryness to dive a syrup. The syrup was purified by column chromatography on silica gel to give crystals. Recrystallization from ethyl acetate-benzene afforded colorless crystals ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]- methyl]benzimidazole-7-carboxylate (0.35 g, 45%), M.P. 158-159°C.
Ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]-methyl]benzimidazole- 7-carboxylate (0.24 g) was stirred with 1 N NaOH (1.5 ml) in ethanol (4 ml) for 1 hours at 80°C. The reaction mixture was concentrated, and the concentrate was exrtacted with water and ethyl acetate. The aqueous layer was adjusted to pH 3-4 with 1 N HCl to give crystals. Recrystallization from ethyl acetate-benzene afforded colorless crystals of 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]-methyl]benzimidazole-7-carboxylic acid (0.15 g, 67%), M.P. 183-185°C.
To a solution of 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]- methyl]benzimidazole-7-carboxylic acid (2.07 g) in methylene chloride (10 ml) were added trityl chloride (1.59 g) and triethylamine (0.8 ml). The mixture was stirred at room temperature for 1 hour. The mixture was washed with water and concentrated to dryness. The residue was purified by column chromatography on silica gel to give crystals. Recrystallization from ethyl acetate-benzene afforded colorless crystals 2-ethoxy-1-[[2'-(N-triphenylmethyltetrazol-5-yl)biphenyl-4-yl]-methyl]benzimidazole-7-carboxylic acid (2.12 g, 66%), M.P. 168-170°C.
To a solution 2-ethoxy-1-[[2'-(N-triphenylmethyltetrazol-5-yl)biphenyl-4-yl]- methyl]benzimidazole-7-carboxylic acid (0.5 g) in DMF (5 ml) were added potassium carbonate (0.12 g) and cyclohexyl 1-iodoethyl carbonate (0.26 g). The mixture was stirred at room temperature for 1 hour. To the mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried. After removal of the solvent, the residue was dissolved in methanol (10 ml) and to solution was added 1 N HCl (2 ml). The mixture was stirred at room temperature for 1 hour. After removal of the solvent, the residue was purified by column chromatography on silica gel to give colorless powder (0.21 g), M.P. 103-106°C. The mixture was stirred for 3 hours at room temperature. To the powder (1 g) obtained as above was added ethanol (6 ml). The mixture was stirred for 3 hours at room temperature and allowed to stand under ice-cooling. The mixture was then stirred for 1 hour at temperature not higher than 10°C. Resultant crystals were collected and washed with cold ethanol. The crystals were dried at 25°C for 9 hours under reduced pressure, then at 35°C for further 18 hours to obtain white powdery crystal 1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1- [[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-benzimidazole-7-carboxylate (0.94 g, M.P. 158-166°C).

brand name

Atacand (AstraZeneca).

Therapeutic Function

Antihypertensive

General Description

Pharmaceutical secondary standards for application in quality control provide pharma laboratories and manufacturers with a convenient and cost-effective alternative to the preparation of in-house working standards

Biochem/physiol Actions

Candesartan cilexetil is the prodrug form of the potent angiotensin II receptor antagonist, candesartan. The prodrug is cleaved by esterases within the intestine to liberate the active molecule.

Clinical Use

Angiotensin-II antagonist:

Hypertension

Heart failure

Side effects

Candesartan cilexetil may lead to various kinds of adverse reactions including headache, back pain, dizziness, upper respiratory tract infection, pharyngitis, rhinitis, bronchitis, coughing, sinusitis, nausea, abdominal pain, diarrhea, vomiting, arthralgia and albuminuria. It should be warned that candesartan cilexetil might have remarkable fetal toxicity. Therefore, upon pregnancy, candesartan cilexetil should be discontinued. It could also cause hypotension for heart-failure patients.

Drug interactions

Potentially hazardous interactions with other drugs
Anaesthetics: enhanced hypotensive effect.
Analgesics: antagonism of hypotensive effect and increased risk of renal impairment with NSAIDs; hyperkalaemia with ketorolac and other NSAIDs.
Antihypertensives: increased risk of hyperkalaemia hypotension and renal impairment with ACE-Is and aliskiren.
Ciclosporin: increased risk of hyperkalaemia and nephrotoxicity. Diuretics: enhanced hypotensive effect; hyperkalaemia with potassium-sparing diuretics. ESAs: increased risk of hyperkalaemia; antagonism of hypotensive effect. Lithium: reduced excretion, possibility of enhanced lithium toxicity. Potassium salts: increased risk of hyperkalaemia. Tacrolimus: increased risk of hyperkalaemia and nephrotoxicity

Metabolism

Candesartan is mainly eliminated unchanged via urine and bile and only to a minor extent eliminated by hepatic metabolism (CYP2C9). The renal elimination of candesartan is both by glomerular filtration and active tubular secretion. Following an oral dose of 14C-labelled candesartan cilexetil, approximately 26% of the dose is excreted in the urine as candesartan and 7% as an inactive metabolite while approximately 56% of the dose is recovered in the faeces as candesartan and 10% as the inactive metabolite.