Irbesartan

Absorption

Irbesartan is 60-80% bioavailable with a Tmax of 1.5-2hours. Taking irbesartan with food does not affect the bioavailability.
In one study, healthy subjects were given single or multiple oral doses of 150mg, 300mg, 600mg, and 900mg of irbesartan. A single 150mg dose resulted in an AUC of 9.7±3.0μg\?hr/mL, a Tmax of 1.5 hours, a half life of 16±7 hours, and a Cmax of 1.9±0.4μg/mL. A single 300mg dose resulted in an AUC of 20.0±5.2μg\?hr/mL, a Tmax of 1.5 hours, a half life of 14±7 hours, and a Cmax of 2.9±0.9μg/mL. A single 600mg dose resulted in an AUC of 32.6±11.9μg\?hr/mL, a Tmax of 1.5 hours, a half life of 14±8 hours, and a Cmax of 4.9±1.2μg/mL. A single 900mg dose resulted in an AUC of 44.8±20.0μg\?hr/mL, a Tmax of 1.5 hours, a half life of 17±7 hours, and a Cmax of 5.3±1.9μg/mL.
Multiple 150mg doses resulted in an AUC of 9.3±3.0μg\?hr/mL, a Tmax of 1.5 hours, a half life of 11±4 hours, and a Cmax of 2.04±0.4μg/mL. Multiple 300mg doses resulted in an AUC of 19.8±5.8μg\?hr/mL, a Tmax of 2.0 hours, a half life of 11±5 hours, and a Cmax of 3.3±0.8μg/mL. Multiple 600mg doses resulted in an AUC of 31.9±9.7μg\?hr/mL, a Tmax of 1.5 hours, a half life of 15±7 hours, and a Cmax of 4.4±0.7μg/mL. Multiple 900mg doses resulted in an AUC of 34.2±9.3μg\?hr/mL, a Tmax of 1.8 hours, a half life of 14±6 hours, and a Cmax of 5.6±2.1μg/mL.

Toxicity

The oral TDLO in humans is 30mg/kg/6W.
Symptoms of overdose include hypotension and tachycardia or bradycardia. Terlipressin may be given to treat hypotension and tachycardia if conventional vasopressors fail to control blood pressure.

Description

Avapro was launched in Germany, the UK and the US for hypertension. It can be prepared in six steps starting with cyclopentanone or in three steps from 1- aminocyclopentanecarboxylic acid ethyl ester and pentanimidic ethyl ester. Avapro is an angiotensin Ⅱ receptor antagonist that is non-competitive and selective for AT, subtypes and has no AT₂ activity at postsynaptic receptors compared to presynatpic. It has no affinity for various non angiotensin Ⅱ receptor types in binding, no interaction with calcium channels or antiports, and no affinity for α₁- and α₂--adrenoreceptors, serotonergic receptors, muscarinic m₁ and m₂ or other receptors. It is as potent as saralasin but with no agonist activity and is 10 times more potent than DuP753 in rats. It is similar in efficacy to enalapril (in those with severe hypertension) and atenolol, while more effective than losartan for mild to moderate hypertension.

Chemical properties

Crystalline Solid

The Uses of Irbesartan

Irbesartan is an angiotensin II type 1 (AII1) receptor antagonist. It is indicated for the treatment of hypertension and diabetic nephropathy in patients with type 2 diabetes mellitus and hypertension who have elevated serum creatinine and proteinuria (>300 mg/day). Irbesartan is also used as a second-line agent for the treatment of hypertension and diabetic nephropathy. In addition, Irbesartan is an antidepressant.

Indications

Irbesartan is indicated to treat hypertension and diabetic nephropathy in hypertensive patients with type 2 diabetes, elevated serum creatinine, and proteinuria. A combination product with hydrochlorothiazide is indicated for hypertension in patients with uncontrolled hypertension with monotherapy or first line in patients not expected to be well controlled with monotherapy.

Background

Irbesartan is an angiotensin receptor blocker (ARB) indicated to treat hypertension or diabetic nephropathy. It can also be used as part of a combination product with hydrochlorothiazide for patients not well controlled or not expected to be well controlled on monotherapy. Unlike angiotensin converting enzyme inhibitors, ARBs are not associated with a dry cough.
Irbesartan was granted FDA approval on 30 September 1997.

What are the applications of Application

Irbesartan is an angiotensin II type 1 (AII1)-receptor antagonist

Definition

ChEBI: A biphenylyltetrazole that is an angiotensin II receptor antagonist used mainly for the treatment of hypertension.

Manufacturing Process

1. Synthesis of 2-n-Butyl-4-spirocyclopentane-2-imidazolin-5-one
Method 1:
The ethyl ester of 1-aminocyclopentanecarboxylic acid is prepared according to Adkins and Billica (J. Amer. Chem. Soc., 1948, 70, 3121).
Ethyl valerimidate hydrochloride is prepared according to Mac Elvain (J. Amer. Chem. Soc., 1942, 64, 1825-1827) and then freed from its hydrochloride by reaction with potassium carbonate and extraction with CH2Cl2.
The ethyl ester of 1-aminocyclopentanecarboxylic acid (1.57 g) and ethyl valerimidate (1.56 g) are dissolved in 12 ml of xylene containing 6 drops of acetic acid. After refluxing for 6.5 h, the reaction medium is concentrated under vacuum, the residue is chromatographed on silica gel using a chloroform/methanol/acetic acid mixture (94/4/2; v/v/v) as the eluent. The fraction containing the expected product is evaporated several times in the presence of xylene and then benzene in order to remove the acetic acid. 1.91 g of 2-n-butyl-4-spirocyclopentane-2-imidazolin-5-one are obtained in the form of a thick oil.
Method 2:
1.97 g of sodium cyanide are dissolved in 3.9 ml of water in a roundbottomed flask and a solution containing 2.33 g of ammonium chloride in 5.9 ml of water and 3.5 ml of 20% aqueous ammonia is added; finally, 3 g of cyclopentanone in 3.8 ml of methanol are added to the flask. After stirring for 1.5 h, the mixture is heated at 60°C for 45 min, heating is then stopped, stirring is continued for 45 min and the mixture is then cooled to 25°C. It is extracted several times with methylene chloride.
The 1-aminocyclopentanenitrile obtained is dissolved in 300 ml of acetone, and a solution of 2.25 g of oxalic acid dihydrate in 200 ml of acetone is added, with stirring. The precipitate of 1-aminocyclopentanenitrile formed is filtered off.
5.1 g of the oxalate obtained in the previous step are treated with 7.65 ml of concentrated sulfuric acid (d = 1.84) over 45 min, with stirring. The evolution of a gas is observed and the temperature rises to 100°C. The mixture is cooled to about 35°C and poured into a mixture of ice and concentrated aqueous ammonia (10 g/2.8 ml). The suspension formed is extracted with chloroform containing 5% of methanol. The 1-aminocyclopentanecarboxamide was obtained.
3 g of the compound prepared in the previous step are placed in 70 ml of anhydrous THF and 3.3 ml of triethylamine, and 3 ml of valeryl chloride in 10 ml of anhydrous THF are added, with stirring. A white suspension is formed. The intermediate which is formed, but not isolated, is 1-(Nvaleryl)aminocyclopentanecarboxamide. 6 g of potassium hydroxide pellets, 7 ml of water and 16 ml of methanol are added. The mixture is refluxed for 2.5 h and 9 g of ammonium chloride are then added. After stirring for 15 min, the mixture is concentrated under vacuum. The residue of the 2-n-butyl-4- spirocyclopentane-2-imidazolin-5-one obtained is taken up in water and extracted with ethyl acetate.
2. Synthesis of 2-n-butyl-4-spirocyclopentane-1-[(2'-(tetrazol-5-yl)biphenyl-4- yl)-methyl]-2-imidazolin-5-one
A mixture containing 250 mg of sodium hydride (as an 80% dispersion in mineral oil) and 5 ml of DMF is prepared under a nitrogen atmosphere and a solution containing 0.97 g of 2-n-butyl-4-spirocyclopentane-2-imidazolin-5- one in 10 ml of DMF is added dropwise. The mixture is stirred for 30 min at 20°C and a solution of 1.5 g of 4-bromomethyl-2'-cyanobiphenyl in 10 ml of DMF is then added. After stirring for 1 h at 20°C, the DMF is evaporated off under reduced pressure, the residue is then taken up with ethyl acetate,filtered and evaporated. The residue of 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-nbutyl-4-spirocyclopentane-2-imidazolin-5-one is purefied by chromatography
1.56 g of the previous product, 2.6 g of tributyltin azide and 30 ml of xylene are refluxed for 66 h. The xylene is then evaporated off and the residue is dissolved in 20 ml of CH2Cl2 and 5 ml of THF with the addition of 0.8 ml of 10 N sodium hydroxide solution and, after stirring for 30 min, 2.5 g of trityl chloride, and the mixture is stirred for 26 h. After evaporation of the solvents, the residue is taken up in ethyl acetate in ethyl acetate, washed with water and then with a 3% solution of potassium bisulfate and water. It is dried and evaporated. The residue is chromatographed on alumina using a hexane/ethyl acetate mixture (9/1; v/v) as the eluent to give 1.97 g of the 2-n-butyl-4- spirocyclopentane-1-[(2'-(triphenylmethyltetrazol-5-yl)biphenyl-4-yl)methyl]- 2-imidazolin-5-one. Melting point 150-152°C.
1.96 g of the product prepared in the previous step are dissolved in 10 ml of methanol and 10 ml of THF. After the reaction medium has been cooled to 5°C, 1.5 ml of 4 N hydrochloric acid are added and the mixture is stirred for 3 h at 20°C and 1 h at 30°C. After evaporation of the solvents, the residue is taken up in water and the pH is brought to 12 by the addition of 10 N sodium hydroxide solution. The aqueous phase is extracted with ether, toluene and ether again. The aqueous phase is acidified to pH 2 by the addition of 1 N hydrochloric acid and then extracted with ethyl acetate and the extract is evaporated. The aqueous phase is acidified to pH 2 by the addition of 1 N hydrochloric acid and then extracted with ethyl acetate and the extract is dried and evaporated. The white solid obtained is dried at 50°C under 0.05 mm of mercury to give 840 mg of the 2-n-butyl-4-spirocyclopentane-1-[(2'- (tetrazol-5-yl)biphenyl-4-yl)methyl]-2-imidazolin-5-one. Melting point 180- 181°C.

brand name

Avapro (Sanofi Aventis);Aprovel/Avapro.

Therapeutic Function

Antihypertensive

General Description

Irbesartan, 2-butyl-3-[[29-(1H-tetrazol-5-yl)[1,19-biphenyl]-4-yl]methyl]1,3-diazaspiro[4,4]non-1en-4-one (Avapro), like losartan, possesses the acidic tetrazolesystem, which most likely plays a role, similar to the acidicgroups of angiotensin II, in binding to the angiotensin II receptor.In addition, the biphenyl system that serves to separatethe tetrazole from the aliphatic nitrogen is still present.A major difference in this agent is that it does not possessthe acidic side chain. Even so, irbesartan has good affinityfor the angiotensin II receptor because of hydrogen bondingwith the carbonyl moiety of the amide system. Also, thisparticular agent does not require metabolic activation ascandesartan does.

Biochem/physiol Actions

Irbesartan is an angiotensin II type 1 (AT1) receptor antagonist with antihypertensive activity. It also elicits selective peroxisome proliferator-activated receptor γ (PPARγ)-modulating activity and possesses anti-inflammatory properties. Irbesartan shows protective cardiovascular effects and provides protection against chronic glomerulonephritis.

Pharmacokinetics

Irbesartan is an angiotensin receptor blocker used to treat hypertension and diabetic nephropathy. It has a long duration of action as it is usually taken once daily and a wide therapeutic index as doses may be as low as 150mg daily but doses of 900mg/day were well tolerated in healthy human subjects.

Clinical Use

Angiotensin-II receptor antagonist:

Hypertension

Diabetic nephropathy

Veterinary Drugs and Treatments

Although experience in veterinary medicine is minimal irbesartan may be useful in treating canine hypertension associated with renal insufficiency. It may be effective in treating heart failure when dogs are unable to tolerate ACE inhibitors, but documentation for this use is lacking. One study, using very high irbesartan dosages (60 mg/kg PO twice daily) in dogs with subacute mitral regurgitation, demonstrated no improvement in left ventricular function or prevention of left ventricular remodeling (Perry, Wei et al. 2002).

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

Irbesaran is largely metabolized by glucuronidation and oxidation in the liver. The majority of metabolism occurs through the action of CYP2C9 with a negligible contribution from CYP3A4. Some hydroxylation also occurs in irbesartan metabolism.
Irbesartan can be glucuronidated by UGT1A3 to the M8 metabolite, oxidized to the M3 metabolite, or hydroxylated by CYP2C9 to one of the M4, M5, or M7 metabolites. The M4, M5, and M7 metabolites are all hydroxylated to become the M1 metabolite, which is then oxidized to the M2 metabolite. The M4 metabolite can also be oxidized to the M6 metabolite before hydroxylation to the M2 metabolite. Finally, the minor metabolite SR 49498 is generated from irbesartan by an unknown mechanism.

Side Effects

Common side effects of Irbesartan include: feeling dizzy, headache, feeling sick (nausea), sickness (vomiting), diarrhoea, joint or muscle pain. Serious side effects may include liver problems (whites of the eyes or yellowing of the skin), signs of blood or bone marrow disorders, and changes in blood potassium levels (irregular heartbeat, pins and needles, and muscle cramps). In rare cases, Irbesartan may cause a serious allergic reaction.

storage

Store at +4°C