Losartan

Last updated

Losartan
Losartan structure.svg
Losartan-from-xtal-3D-bs-17.png
Clinical data
Pronunciation /loʊˈsɑːrtən/
Trade names Cozaar, others
AHFS/Drugs.com Monograph
MedlinePlus a695008
License data
Pregnancy
category
Routes of
administration 		By mouth
Drug class Angiotensin II receptor antagonist
ATC code
Legal status
Legal status
  • US: WARNING [2] Rx-only [3]
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 25–35%
Protein binding 99.7% (primarily albumin)
Metabolism Liver (CYP2C9, CYP3A4)
Elimination half-life 1.5–2 hours
Excretion Kidney 13–25%, bile duct 50–60%
Identifiers
  • (2-butyl-4-chloro-1-{[2'-(2H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazol-5-yl)methanol
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.110.555 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C22H23ClN6O
Molar mass 422.92 g·mol−1
3D model (JSmol)
  • CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nn[nH]n2)cc1
  • InChI=1S/C22H23ClN6O/c1-2-3-8-20-24-21(23)19(14-30)29(20)13-15-9-11-16(12-10-15)17-6-4-5-7-18(17)22-25-27-28-26-22/h4-7,9-12,30H,2-3,8,13-14H2,1H3,(H,25,26,27,28) Yes check.svgY
  • Key:PSIFNNKUMBGKDQ-UHFFFAOYSA-N Yes check.svgY
   (verify)

Losartan, sold under the brand name Cozaar among others, is a medication used to treat high blood pressure (hypertension). [4] It is in the angiotensin receptor blocker (ARB) family of medication, and is considered protective of the kidneys. Besides hypertension, it is also used in diabetic kidney disease, heart failure, and left ventricular enlargement. [4] It comes as a tablet that is taken by mouth. [4] It may be used alone or in addition to other blood pressure medication. [4] Up to six weeks may be required for the full effects to occur. [4]

Contents

Common adverse effects include muscle cramps, stuffy nose, dizziness, cough, high blood potassium, and anemia. [4] Severe adverse effects may include angioedema, low blood pressure, and kidney problems. [4] Use during pregnancy may result in harm to the baby. [4] [1] Use is not recommended during breastfeeding. [1] It works by blocking angiotensin II. [4]

Losartan was patented in 1986, and approved for medical use in the United States in 1995. [4] [5] It is on the World Health Organization's List of Essential Medicines. [6] It is available as a generic medication. [7] In 2021, it was the eighth most commonly prescribed medication in the United States, with more than 55 million prescriptions. [8] [9] A version combined with hydrochlorothiazide is available [4] which, in 2021, was the 87th most commonly prescribed medication in the United States, with more than 8 million prescriptions. [8] [10]

Chemistry

Losartan potassium is chemically described as 2-butyl-4-chloro-1-[p-(o-1H-tetrazol-5-ylphenyl)benzyl]imidazole-5-methanol monopotassium salt. Its empirical formula is C22H23CIKN6O , and its molecular weight is 422.9. [11]

Losartan is generally marketed as the (basic) potassium salt of the aromatized negatively charged tetrazole, called "losartan potassium". [12] The molecule has an extended biphenyl group with a tetrazole which is being used in place of the carboxylic acid as a bioisostere. [13]

Medical uses

Losartan is used for hypertension, including in people with left ventricular hypertrophy (enlarged heart muscle), and kidney dysfunction among type II diabetics. [3] It may also delay progression of diabetic nephropathy. It is a suitable pharmacological agent for the reduction of renal disease progression in patients with type 2 diabetes, hypertension, and microalbuminuria (>30 mg/24 hours) or proteinuria (>900 mg/24 hours). [14]

Although evidence shows calcium channel blockers and thiazide-type diuretics are preferred first-line treatments for most people (due to both efficacy and cost), an angiotensin II receptor antagonist such as losartan is recommended as first-line treatment in people under the age of 55 who cannot tolerate an ACE inhibitor. [15] One study demonstrated losartan was superior to atenolol in the primary prevention of adverse cardiovascular events (myocardial infarction or stroke), with a reduction in cardiovascular morbidity and mortality for a comparable reduction in blood pressure. The maximal effects on blood pressure usually occur within 3–6 weeks of starting losartan. [16]

Adverse effects

The most common adverse effects for losartan in adults are upper respiratory infections, dizziness, and back pain. [3] People with type 2 diabetes and kidney disease may experience diarrhea, fatigue, low blood pressure, low blood glucose, elevated potassium, chest pain, or allergic reaction. [3] Losartan should not be taken by people who are diabetic and taking aliskiren. [3] Anemia may occur, due to inhibition of the renin–angiotensin system. [17] As with other angiotensin receptor blockers, losartan may injure the liver, although this effect appears to be rare. [18] Electrolyte imbalances may occur in people with kidney problems who take losartan. [3] Adverse outcomes do not differ by sex, age or race. [3]

Pregnancy

In October 2014, the U.S. Food and Drug Administration (FDA) issued a black box warning that losartan can cause fetal toxicity, and should be discontinued as soon as pregnancy is detected. [19] [3] Using losartan while pregnant could result in fetal injury or death. [19] [3]

Overdose

Overdosing would most likely result in decreased blood pressure, which could manifest as an increased heart rate, dizziness, feeling light headed, or loss of consciousness. Mice studies showed that lethality occurred at about 44 to 170 times the maximum recommended dose after the mice weights were taken into account. [3]

Interactions

Losartan may have adverse interactions with phenobarbital, rifampin, or fluconazole, possibly inhibiting its blood pressure-lowering effects. [3]

Contamination

Between November 2018 and September 2019, the FDA announced multiple recalls of tablets containing losartan by Sandoz, Torrent Pharmaceuticals, Hetero Labs, Camber Pharmaceuticals, Legacy Pharmaceutical Packaging, Teva Pharmaceuticals, Vivimed Life Sciences, and Macleods Pharmaceutical Limited due to detection of one of the possible carcinogens N-nitrosodiethylamine, N-methylnitrosobutyric acid, or N-nitroso-N-methyl-4-aminobutyric acid in the active pharmaceutical ingredient (API). [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37]

Mechanism of action

Renin-angiotensin-aldosterone system (RAAS) Renin-angiotensin-aldosterone system.svg
Renin-angiotensin-aldosterone system (RAAS)

Losartan is a selective, competitive angiotensin II receptor type 1 (AT1) antagonist, reducing the end organ responses to angiotensin II. Losartan administration results in a decrease in total peripheral resistance (afterload) and cardiac venous return (preload). All of the physiological effects of angiotensin II, including release of aldosterone, are antagonized in the presence of losartan. Reduction in blood pressure occurs independently of the status of the renin–angiotensin system. As a result of losartan dosing, plasma renin activity increases due to removal of the angiotensin II feedback. Renin is released from the kidneys when there is reduced renal arterial pressure, sympathetic activation, or increased sodium delivery to the distal renal tubule. [38] Renin then acts by converting angiotensinogen to angiotensin I; angiotensin converting enzyme (ACE) converts angiotensin I to angiotensin II; angiotensin II causes vasoconstriction and aldosterone release. [38] Aldosterone serves to retain sodium from the distal renal tubule. Sodium retention ultimately results in increased blood pressure. [39] Therefore, the use of angiotensin II receptor antagonists like losartan result in blocking the downstream effect of renin, angiotensin II, and ultimately decreasing blood pressure.

Angiotensin II receptor antagonists include losartan, valsartan, azilsartan, candesartan, eprosartan, irbesartan, olmesartan, and telmisartan. They all have the same mechanism of action and potentially inhibit the actions of angiotensin better than ACE inhibitors, such as lisinopril, because there are other enzymes than ACE that have the capability of producing angiotensin II. [38]

Losartan is a uricosuric. As a specific inhibitor of the urate transporter 1 (SLC22A12, URAT1), losartan blocks the uptake of uric acid into cells, thus leaving more available in the bloodstream to be filtered and excreted by the kidneys. [40] Because losartan can cause hyperkalemia, individuals should not use potassium supplements or salt substitutes containing potassium without appropriate monitoring by a physician. [41]

Pharmacokinetics

Losartan is well absorbed following oral administration and undergoes significant first-pass metabolism to produce the 5-carboxylic acid metabolite, designated as EXP3174. About 14% of an oral dosage is converted to this metabolite, which is long-acting (6 to 8 hr) and a noncompetitive antagonist at the AT1 receptor, contributing to the pharmacological effects of losartan. EXP3174 is 10-40 times more potent in blocking AT1 receptors than losartan. In addition, the binding to the target enzyme is pH-sensitive, and the negatively-charged tetrazole ring, which is similar in size to the negative carboxylic acid derivative, may contribute to the activity of the drug. [42]

Losartan's bioavailability is about 33%. [43]

Metabolism is primarily by cytochrome P450 isoenzymes CYP2C9 and CYP3A4. [44] Peak plasma concentrations of losartan and EXP3174 occur about one hour and three to four hours, respectively, after an oral dose. [45] Both losartan and EXP3174 are more than 98% bound to plasma proteins. [46] Losartan is excreted in the urine, and in the feces via bile, as unchanged drug and metabolites. [47] About 4% of an oral dose is excreted unchanged in urine, and about 6% is excreted in urine as the active metabolite. [48] The terminal elimination half lives of losartan and EXP3174 are about 1.5 to 2.5 hours and 3 to 9 hours, respectively. [49]

Losartan and other angiotensin-receptor antagonists exhibit fetal toxicity and should be avoided during pregnancy, particularly in the second and third trimesters. [50]

History

Related Research Articles

<span class="mw-page-title-main">Hydrochlorothiazide</span> Diuretic medication

Hydrochlorothiazide, sold under the brand name Hydrodiuril among others, is a diuretic medication used to treat hypertension and swelling due to fluid build-up. Other uses include treating diabetes insipidus and renal tubular acidosis and to decrease the risk of kidney stones in those with a high calcium level in the urine. Hydrochlorothiazide is taken by mouth and may be combined with other blood pressure medications as a single pill to increase effectiveness. Hydrochlorothiazide is a thiazide medication which inhibits reabsorption of sodium and chloride ions from the distal convoluted tubules of the kidneys, causing a natriuresis. This initially increases urine volume and lowers blood volume. It is believed to reduce peripheral vascular resistance.

<span class="mw-page-title-main">Angiotensin II receptor blocker</span> Group of pharmaceuticals that modulate the renin–angiotensin system

Angiotensin II receptor blockers (ARBs), formally angiotensin II receptor type 1 (AT1) antagonists, also known as angiotensin receptor blockers, angiotensin II receptor antagonists, or AT1 receptor antagonists, are a group of pharmaceuticals that bind to and inhibit the angiotensin II receptor type 1 (AT1) and thereby block the arteriolar contraction and sodium retention effects of renin–angiotensin system.

<span class="mw-page-title-main">Irbesartan</span> Chemical compound

Irbesartan, sold under the brand name Avapro among others, is a medication used to treat high blood pressure, heart failure, and diabetic kidney disease. It is a reasonable initial treatment for high blood pressure. It is taken by mouth. Versions are available as the combination irbesartan/hydrochlorothiazide.

<span class="mw-page-title-main">Ranitidine</span> Medication that decreases stomach acid

Ranitidine, sold under the brand name Zantac among others, is a medication used to decrease stomach acid production. It is commonly used in treatment of peptic ulcer disease, gastroesophageal reflux disease, and Zollinger–Ellison syndrome. It can be given by mouth, injection into a muscle, or injection into a vein. In September 2019, the probable carcinogen N-nitrosodimethylamine (NDMA) was discovered in ranitidine products from a number of manufacturers, resulting in recalls.

<span class="mw-page-title-main">Lisinopril</span> Medication used to treat high blood pressure and heart failure

Lisinopril is a medication belonging to the drug class of angiotensin-converting enzyme (ACE) inhibitors and is used to treat high blood pressure, heart failure, and heart attacks. For high blood pressure it is usually a first-line treatment. It is also used to prevent kidney problems in people with diabetes mellitus. Lisinopril is taken by mouth. Full effect may take up to four weeks to occur.

<span class="mw-page-title-main">Quinapril</span> ACE inhibitor used in the treatment of hypertension and congestive heart failure

Quinapril, sold under the brand name Accupril by the Pfizer corporation. It a medication used to treat high blood pressure (hypertension), heart failure, and diabetic kidney disease. It is a first line treatment for high blood pressure. It is taken by mouth.

<span class="mw-page-title-main">Triamterene</span> Chemical compound

Triamterene is a potassium-sparing diuretic often used in combination with thiazide diuretics for the treatment of high blood pressure or swelling. The combination with hydrochlorothiazide, is known as hydrochlorothiazide/triamterene.

<span class="mw-page-title-main">Valsartan</span> Angiotensin II receptor antagonist

Valsartan, sold under the brand name Diovan among others, is a medication used to treat high blood pressure, heart failure, and diabetic kidney disease. It belongs to a class of medications referred to as angiotensin II receptor blockers (ARBs). It is a reasonable initial treatment for high blood pressure. It is taken by mouth.

<span class="mw-page-title-main">Olmesartan</span> Angiotensin II receptor antagonist

Olmesartan, sold under the brand name Benicar among others, is a medication used to treat high blood pressure (hypertension). It is taken by mouth. Versions are available as the combination olmesartan/hydrochlorothiazide and olmesartan/amlodipine.

Torrent Pharmaceuticals Ltd is an Indian multinational pharmaceutical company, owned by the Rs 37,000 crore Torrent Group and headquartered in Ahmedabad. It was promoted by U. N. Mehta, initially as Trinity Laboratories Ltd, and was later renamed Torrent Pharmaceuticals Ltd.

<span class="mw-page-title-main">Aliskiren</span> Medication

Aliskiren is the first in a class of drugs called direct renin inhibitors. It is used for essential (primary) hypertension. While used for high blood pressure, other better studied medications are typically recommended due to concerns of higher side effects and less evidence of benefit.

<span class="mw-page-title-main">Amlodipine/valsartan</span> Antihypertensive medication

Amlodipine/valsartan, sold under the brand name Exforge among others, is a blood pressure lowering combination drug. It contains amlodipine, as the besilate, a dihydropyridine-type calcium channel blocker, and valsartan, an angiotensin II receptor antagonist. This combination is usually well tolerated and effective for the reduction of blood pressure.

<i>N</i>-Nitrosodiethylamine Chemical compound

N-Nitrosodiethylamine (NDEA) is an organic compound with the formula Et2NNO (Et = C2H5). A member of the nitrosamines, it is a light-sensitive, volatile, clear yellow oil that is soluble in water, lipids, and other organic solvents. It has an amine or aromatic odor. It is used as gasoline and lubricant additive, antioxidant, and stabilizer for industry materials. When heated to decomposition, N-nitrosodiethylamine emits toxic fumes of nitrogen oxides. N-Nitrosodiethylamine affects DNA integrity, probably by alkylation, and is used in experimental research to induce liver tumorigenesis. It is carcinogenic and mutagenic. NDEA has also been found to perturb amino acid biosynthesis including arginine, as well as DNA damage repair and mitochondrial genome maintenance in yeast.

<span class="mw-page-title-main">Azilsartan</span> Chemical compound

Azilsartan, sold under the brand name Edarbi among others, is used for the treatment of hypertension. It is used as the prodrug azilsartan medoxomil, is an angiotensin II receptor antagonist, and was developed by Takeda.

Telmisartan/hydrochlorothiazide, sold under the brand name Micardis HCT among others, is a fixed-dose combination medication used to treat high blood pressure. It is a combination of telmisartan an angiotensin II receptor antagonist with hydrochlorothiazide a diuretic. It may be used if telmisartan by itself is not sufficient. It is taken by mouth.

<span class="mw-page-title-main">Valsartan/hydrochlorothiazide</span> Chemical compound

Valsartan/hydrochlorothiazide, sold under the brand name Diovan HCT among others, is a medication used to treat high blood pressure when valsartan is not sufficient. It is a combination of valsartan, an angiotensin receptor blocker with hydrochlorothiazide, a diuretic. It is taken by mouth.

Losartan/hydrochlorothiazide, sold under the brand name Hyzaar among others, is a fixed-dose combination medication used to treat high blood pressure when losartan is not sufficient. It consists of losartan and hydrochlorothiazide. It is taken by mouth.

<span class="mw-page-title-main">Aurobindo Pharma</span> Indian multinational pharmaceutical company

Aurobindo Pharma Limited is an Indian multinational pharmaceutical manufacturing company headquartered in HITEC City, Hyderabad, India. The company manufactures generic pharmaceuticals and active pharmaceutical ingredients. The company’s area of activity includes six major therapeutic and product areas: antibiotics, anti-retrovirals, cardiovascular products, central nervous system products, gastroenterologicals, and anti-allergics. The company markets these products in over 125 countries. Its marketing partners include AstraZeneca and Pfizer.

<span class="mw-page-title-main">Taro Pharmaceuticals</span> Generic pharmaceutical company

Taro Pharmaceutical Industries is an Israeli research-based pharmaceutical manufacturer publicly listed in the New York Stock Exchange. The company has more than 180 of its own drugs sold all over the world, reaching the markets of over 25 countries. The company's products are mainly sold in the United States, Canada and Israel. Taro Pharmaceutical Industries is reported to be on steady growth since 2008.

Aliskiren/hydrochlorothiazide, sold under the brand name Tekturna HCT among others, is a fixed-dose combination medication for the treatment of hypertension. It contains aliskiren, a renin inhibitor, and hydrochlorothiazide, a diuretic. It is taken by mouth.

References

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  2. ↑ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA . Retrieved 22 October 2023.
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  12. ↑ "See negatively charged tetrazole structure". Archived from the original on 22 January 2021. Retrieved 21 October 2017.
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  29. ↑ "Macleods Pharmaceutical Limited Issues Voluntary Nationwide Consumer Level Recall of Losartan Potassium 50mg and Losartan Potassium/Hydrochlorothiazide combination Tablets 50mg/12.5mg, 100mg/12.5mg and 100mg/25mg due to detection of NMBA (N-Nitroso-N-Methyl-4-aminobutyric acid) Impurity". U.S. Food and Drug Administration (FDA). 26 June 2019. Archived from the original on 1 October 2019. Retrieved 5 October 2019.
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  31. ↑ "Vivimed Life Sciences Pvt Ltd Issues Voluntary Nationwide Recall of Losartan Potassium 25 mg, 50 mg and 100 mg Tablets, USP Due to the Detection of Trace Amounts of N-Nitroso-N-methyl-4-aminobutyric acid (NMBA) Impurity". U.S. Food and Drug Administration (FDA). 3 May 2019. Archived from the original on 13 September 2019. Retrieved 5 October 2019.
  32. ↑ "Teva Pharmaceuticals USA, Inc. Issues Voluntary Nationwide Recall of Losartan Potassium 25 mg and 100 mg Tablets USP, Sold Exclusively to Golden State Medical Supply". U.S. Food and Drug Administration (FDA). 26 April 2019. Archived from the original on 13 September 2019. Retrieved 5 October 2019.
  33. ↑ "Legacy Pharmaceutical Packaging, LLC Issues Voluntary Nationwide Recall of Losartan Potassium Tablets, USP, 25mg, 50mg, And 100mg Due to The Detection of Trace Amounts Of N-Nitroso N-Methyl 4-Amino Butyric Acid (NMBA) Impurity Found in The Active Pharmaceutical Ingredient (API)". U.S. Food and Drug Administration (FDA). 19 March 2019. Archived from the original on 7 September 2019. Retrieved 5 October 2019.
  34. ↑ "Legacy Pharmaceutical Packaging, LLC Issues Voluntary Nationwide Recall of Losartan Potassium Tablets, USP, 25mg, 50mg, and 100mg Due to the Detection of Trace Amounts of N-Nitroso N-Methyl 4-Amino Butyric Acid (NMBA) Impurity Found in the Active Pharmaceutical Ingredient (API)". U.S. Food and Drug Administration (FDA). 28 March 2019. Archived from the original on 7 September 2019. Retrieved 5 October 2019.
  35. ↑ "Legacy Pharmaceutical Packaging, LLC Issues Voluntary Nationwide Recall of Losartan Potassium Tablets, USP, 50mg Due to the Detection of Trace Amounts of N-Nitroso N-Methyl 4-amino butyric acid (NMBA) Impurity found in the Active Pharmaceutical Ingredient (API)". U.S. Food and Drug Administration (FDA). 15 March 2019. Archived from the original on 7 September 2019. Retrieved 5 October 2019.
  36. ↑ "Camber Pharmaceuticals, Inc. Issues Voluntary Nationwide Recall of Losartan Potassium Tablets, USP, 25 mg, 50 mg and 100 mg Due to the Detection of Trace Amounts of N-Nitroso N-Methyl 4-amino butyric acid (NMBA) Impurity found in the Active Pharmaceutical Ingredient (API)". U.S. Food and Drug Administration (FDA). 28 February 2019. Archived from the original on 7 September 2019. Retrieved 5 October 2019.
  37. ↑ "Macleods Pharmaceuticals Limited Issues Voluntary Nationwide Consumer Level Recall of One Lot (BLM 715A) of Losartan Potassium/Hydrochlorothiazide Combination Tablets 100mg/25mg Due to detection of NDEA (N-Nitrosodiethylamine) Impurity". U.S. Food and Drug Administration (FDA). 22 February 2019. Archived from the original on 7 September 2019. Retrieved 5 October 2019.
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  40. ↑ Hamada T, Ichida K, Hosoyamada M, Mizuta E, Yanagihara K, et al. (1 October 2008). "Uricosuric action of losartan via the inhibition of urate transporter 1 (URAT 1) in hypertensive patients". American Journal of Hypertension. 21 (10): 1157–1162. doi: 10.1038/ajh.2008.245 . PMID   18670416.
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  43. ↑ "DailyMed - LOSARTAN POTASSIUM 25 MG- losartan potassium tablet, film coated LOSARTAN POTASSIUM 50 MG- losartan potassium tablet, film coated LOSARTAN POTASSIUM 100 MG- losartan potassium tablet, film coated". Archived from the original on 27 April 2022. Retrieved 27 April 2022.
  44. ↑ "DailyMed - LOSARTAN POTASSIUM 25 MG- losartan potassium tablet, film coated LOSARTAN POTASSIUM 50 MG- losartan potassium tablet, film coated LOSARTAN POTASSIUM 100 MG- losartan potassium tablet, film coated". Archived from the original on 27 April 2022. Retrieved 27 April 2022.
  45. ↑ "DailyMed - LOSARTAN POTASSIUM 25 MG- losartan potassium tablet, film coated LOSARTAN POTASSIUM 50 MG- losartan potassium tablet, film coated LOSARTAN POTASSIUM 100 MG- losartan potassium tablet, film coated". Archived from the original on 27 April 2022. Retrieved 27 April 2022.
  46. ↑ "DailyMed - LOSARTAN POTASSIUM 25 MG- losartan potassium tablet, film coated LOSARTAN POTASSIUM 50 MG- losartan potassium tablet, film coated LOSARTAN POTASSIUM 100 MG- losartan potassium tablet, film coated". Archived from the original on 27 April 2022. Retrieved 27 April 2022.
  47. ↑ "DailyMed - LOSARTAN POTASSIUM 25 MG- losartan potassium tablet, film coated LOSARTAN POTASSIUM 50 MG- losartan potassium tablet, film coated LOSARTAN POTASSIUM 100 MG- losartan potassium tablet, film coated". Archived from the original on 27 April 2022. Retrieved 27 April 2022.
  48. ↑ "DailyMed - LOSARTAN POTASSIUM 25 MG- losartan potassium tablet, film coated LOSARTAN POTASSIUM 50 MG- losartan potassium tablet, film coated LOSARTAN POTASSIUM 100 MG- losartan potassium tablet, film coated". Archived from the original on 27 April 2022. Retrieved 27 April 2022.
  49. ↑ "DailyMed - LOSARTAN POTASSIUM 25 MG- losartan potassium tablet, film coated LOSARTAN POTASSIUM 50 MG- losartan potassium tablet, film coated LOSARTAN POTASSIUM 100 MG- losartan potassium tablet, film coated". Archived from the original on 27 April 2022. Retrieved 27 April 2022.
  50. ↑ Sica DA, Gehr TW, Ghosh S (2005). "Clinical pharmacokinetics of losartan". Clin Pharmacokinet. 44 (8): 797–814. doi:10.2165/00003088-200544080-00003. PMID   16029066. S2CID   41326620.

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