AT1 Receptor

氯沙坦与血管紧张素 II 竞争与 AT1 受体的结合。抑制 50% 血管紧张素 II 结合的浓度 (IC50) 为 20 nM[1]。氯沙坦 (40 μM) 会影响 ISC，但会阻止 ANGII 对 ISC 的影响[2]。氯沙坦显着降低子宫内膜癌细胞中血管紧张素II介导的细胞增殖。与单独使用每种药物相比，氯沙坦和抗 miR-155 的组合具有显着更强的抗增殖作用[3]。

相对于安慰剂治疗的 Fbn1C1039G/+ 动物，氯沙坦（0.6 g/L，口服）治疗的 Fbn1C1039G/+ 小鼠显示远端空域口径减小。调整氯沙坦和普萘洛尔的剂量以达到可比较的血流动力学效果。 pSmad2 核染色分析表明，氯沙坦拮抗 Fbn1C1039G/+ 小鼠主动脉壁中的 TGF-β 信号传导。氯沙坦可以改善肺部疾病表现，但这一事件似乎与血流动力学改善无关[4]。氯沙坦（10 mg/kg，动脉内注射）可使血液血管紧张素水平增加四到六倍。氯沙坦（10 mg/kg，腹腔注射）使血浆肾素水平增加 100 倍；血浆血管紧张素原水平降低至对照的 24%；血浆醛固酮水平没有变化[5]。

1型（AT1）血管紧张素II（Ang II）受体的拮抗剂增加肾素分泌和血浆Ang II水平，Ang II水平的增加可能会抵消拮抗剂的作用。此外，其他研究人员提出，Ang II水平的反应性增加可能通过刺激2型Ang II受体（AT2）来增加缓激肽（BK）水平。我们通过在6、12和24小时测量循环血管紧张素和BK肽，研究了AT1受体拮抗剂氯沙坦（每12小时动脉内注射10mg/kg）对雄性Sprague-Dawley大鼠的急性影响。急性氯沙坦给药使血液血管紧张素水平增加了四至六倍，但血液BK水平没有变化。我们还研究了氯沙坦给药8天（每12小时腹腔注射10mg/kg）对循环和组织中血管紧张素和BK肽以及血管紧张素转换酶（ACE）水平的影响。氯沙坦使血浆肾素水平增加了100倍；血浆血管紧张素原水平降至对照组的24%；血浆醛固酮水平无变化。氯沙坦给药后，血浆、肾上腺、肺、心脏和主动脉中的Ang II水平分别增加了25倍、8倍、3.5倍、2.4倍和14倍。相比之下，肾脏Ang II水平降至对照组的71%，同时肾脏BK-（1-7）和BK-（1-9）水平降低。除了血液中BK-（1-8）水平降低到对照组的43%外，没有其他组织显示BK肽水平的变化。血浆ACE升高13-50%，但组织ACE水平不变。这些数据表明，氯沙坦对内源性血管紧张素和BK肽的水平具有组织特异性作用，并表明BK水平的增加对氯沙坦的作用没有贡献。内源性肾脏Ang II水平没有反应性增加，表明该组织可能对AT1受体拮抗作用最敏感[5]。

MTT 测定用于量化细胞的活力和增殖。在 96 孔板中，每孔接种 5000 个细胞，并用 200 μL 培养基进行测定。让细胞贴壁过夜后，吸出培养基。将 MTT 以 1 mg/mL 的浓度添加到无血清培养基中后，将混合物在 37°C 下孵育 4 小时。为了溶解甲臜晶体，除去 MTT 溶液后加入 100 μL DMSO。然后，使用酶标仪测量 570 nm 和 600 nm 处的吸光度作为参考。因此，吸光度的变化与细胞存活的程度有关。

Mice of the wild type mate with female Fbn1^C1039G/+ mice at predetermined times. Ocular losartan (0.6 g/L in drinking water; n = 10), propranolol (0.5 g/L; n = 6), or placebo (n = 12) is administered to pregnant female Fbn1^C1039G/+ mice at 14.5 days post-coitum. Up until the age of ten months, therapy is administered during lactation and following weaning. These methods are applied to the sacrifice and examination of mice. In MFS, the current, albeit contentious, standard of care for modulating abnormal growth of the aortic root is β-adrenergic receptor blockade; propranolol and losartan are the comparison drugs. At 7 weeks of age, oral losartan (0.6 g/L in drinking water; n = 5), propranolol (0.5 g/L; n = 7), or a placebo (n = 10) is administered to wild-type and Fbn1^C1039G/+ mice. Following six months of oral treatment, mice are sacrificed.

Absorption, Distribution and Excretion
Losartan is approximately 33% orally bioavailable. Losartan has a Tmax of 1 hour and the active metabolite has a Tmax of 3-4 hours. Taking losartan with food decreases the Cmax but does only results in a 10% decrease in the AUC of losartan and its active metabolite. A 50-80mg oral dose of losartan leads to a Cmax of 200-250ng/mL.
A single oral dose of losartan leads to 4% recovery in the urine as unchanged losartan, 6% in the urine as the active metabolite. Oral radiolabelled losartan is 35% recovered in urine and 60% in feces. Intravenous radiolabelled losartan is 45% recovered in urine and 50% in feces.
The volume of distribution of losartan is 34.4±17.9L and 10.3±1.1L for the active metabolite (E-3174).
Losartan has a total plasma clearance of 600mL/min and a renal clearance of 75mL/min. E-3174, the active metabolite, has a total plasma clearance of 50mL/min and a renal clearance of 25mL/min.
It is not known whether losartan is excreted in human milk, but significant levels of losartan and its active metabolite were shown to be present in rat milk.
Following oral administration, losartan is well absorbed (based on absorption of radiolabeled losartan) and undergoes substantial first-pass metabolism; the systemic bioavailability of losartan is approximately 33%. About 14% of an orally-administered dose of losartan is converted to the active metabolite. Mean peak concentrations of losartan and its active metabolite are reached in 1 hour and in 3-4 hours, respectively. While maximum plasma concentrations of losartan and its active metabolite are approximately equal, the AUC of the metabolite is about 4 times as great as that of losartan. A meal slows absorption of losartan and decreases its Cmax but has only minor effects on losartan AUC or on the AUC of the metabolite (about 10% decreased).
Studies in rats indicate that losartan crosses the blood-brain barrier poorly, if at all.
Both losartan and its active metabolite are highly bound to plasma proteins, primarily albumin, with plasma free fractions of 1.3% and 0.2%, respectively. Plasma protein binding is constant over the concentration range achieved with recommended doses.
For more Absorption, Distribution and Excretion (Complete) data for Losartan (8 total), please visit the HSDB record page.

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Metabolism / Metabolites
Losartan is metabolized to an aldehyde intermediate, E-3179, which is further metabolized to a carboxylic acid, E-3174, by cytochrome P450s like CYP2C9. Losartan can also be hydroxylated to an inactive metabolite, P1. Approximately 14% of losartan is metabolized to E-3174. Losartan can be metabolized by CYP3A4, CYP2C9, and CYP2C10. Losartan can also be glucuronidated by UGT1A1, UGT1A3, UGT1A10, UGT2B7, and UGT 2B17.
Losartan is an orally active agent that undergoes substantial first-pass metabolism by cytochrome P450 enzymes. It is converted, in part, to an active carboxylic acid metabolite that is responsible for most of the angiotensin II receptor antagonism that follows losartan treatment. Losartan metabolites have been identified in human plasma and urine. In addition to the active carboxylic acid metabolite, several inactive metabolites are formed. Following oral and intravenous administration of (14)C-labeled losartan potassium, circulating plasma radioactivity is primarily attributed to losartan and its active metabolite. In vitro studies indicate that cytochrome P450 2C9 and 3A4 are involved in the biotransformation of losartan to its metabolites. Minimal conversion of losartan to the active metabolite (less than 1% of the dose compared to 14% of the dose in normal subjects) was seen in about one percent of individuals studied.
Losartan has known human metabolites that include Losartan carboxylic acid and 2-[5-[2-[4-[[2-butyl-5-chloro-4-(hydroxymethyl)-1H-imidazol-3-ium-3-yl]methyl]phenyl]phenyl]-1,5-dihydrotetrazol-2-yl]-6-(dihydroxymethyl)oxane-3,4,5-triol.

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Biological Half-Life
The terminal elimination half life of losartan is 1.5-2.5 hours while the active metabolite has a half life of 6-9 hours.
The terminal half-life of losartan is about 2 hours and of the metabolite is about 6-9 hours.

Toxicity Summary
IDENTIFICATION AND USE: Losartan is a light yellow solid that is formulated into oral tablets. Losartan is an angiotensin II type 1 (AT1) receptor antagonist. It is used alone or in combination with other classes of antihypertensive agents in the management of hypertension. It is also used to reduce the risk of stroke in patients with hypertension and left ventricular hypertrophy and for the treatment of diabetic nephropathy in patients with type 2 diabetes and a history of hypertension. HUMAN EXPOSURE AND TOXICITY: The most likely manifestations of losartan overdose include hypotension and tachycardia; bradycardia could be encountered if parasympathetic (vagal) stimulation occurs. The use of lorsartan during pregnancy is 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 oligohydramnios may produce fetal limb contractures, craniofacial deformation, and pulmonary hypoplasia. Severe anuria and hypotension that is resistant to both pressor agents and volume expansion may occur in the newborn following in utero exposure to losartan. ANIMAL STUDIES: Losartan potassium was not carcinogenic when administered at maximally tolerated dosages to rats and mice. Female rats given losartan had a slightly higher incidence of pancreatic acinar adenoma. Also, fertility and reproductive performance were not affected in studies with male rats given oral doses of losartan. The administration of toxic dosage levels in females was associated with a significant decrease in the number of corpora lutea/female, implants/female, and live fetuses/female at C-section. The relationship of these findings to drug-treatment is uncertain since there was no effect at these dosage levels on implants/pregnant female, percent post-implantation loss, or live animals/litter at parturition. Losartan has been shown to produce adverse effects in rat fetuses and neonates, including decreased body weight, delayed physical and behavioral development, mortality and renal toxicity. With the exception of neonatal weight gain doses associated with these effects exceeded 25 mg/kg. These findings are attributed to drug exposure in late gestation and during lactation. Losartan was negative in the microbial mutagenesis and V-79 mammalian cell mutagenesis assays and in the in vitro alkaline elution assay and in vitro and in vivo chromosomal aberration assays. In addition, the active metabolite showed no evidence of genotoxicity in the microbial mutagenesis, in vitro alkaline elution assay, and in vitro chromosomal aberration assays.

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Interactions
... This study was undertaken to evaluate how the chronic administration of deoxycortisone acetate (DOCA) modifies the effects of losartan on BP, renal injury, and other variables in /N(G)-nitro-L-arginine methyl ester (L-NAME)/ hypertensive rats. The following groups were used: Control, DOCA, L-NAME, L-NAME + losartan, L-NAME + DOCA, and L-NAME + DOCA + losartan. Tail systolic BP was measured twice a week. After 4-wk evolution, mean arterial pressure and metabolic, morphologic, and renal variables were measured. The final mean arterial pressure values were 116 +/- 6 mm Hg for control, 107 +/- 2 mmHg for DOCA, 151 +/- 5 mmHg for L-NAME, 123 +/- 2 mmHg for L-NAME + losartan, 170 +/- 3 mm Hg for L-NAME + DOCA, and 171 +/- 5.5 mmHg for L-NAME + DOCA + losartan. Losartan prevented microalbuminuria, hyaline arteriopathy, and glomerulosclerosis of L-NAME hypertension but was ineffective in L-NAME + DOCA-treated rats. ... Plasma renin activity was suppressed in the DOCA (0.55 +/- 0.2) and L-NAME + DOCA (0.60 +/- 10.2) groups but unsuppressed in the L-NAME + DOCA + losartan group (5.8 +/- 1). The conclusion is that DOCA blocks the preventive effect of losartan on the increased BP and renal injury of L-NAME hypertension ... These data also suggest that losartan prevents L-NAME hypertension by blocking the activity of systemic Ang II. /Salt not specified/
NSAIDs are known to attenuate the effects of some antihypertensive medications ... A multicenter study assessing the effect of indomethacin on the antihypertensive effects of losartan and captopril /was conducted/. After 4 weeks of placebo washout, hypertensive patients received 6 weeks of active antihypertensive therapy with ... 50 mg losartan once daily (n=111) ... This was followed by 1 week of concomitant therapy with indomethacin (75 mg daily). The primary outcome measure was the change in mean 24-hour ambulatory diastolic blood pressure after the addition of indomethacin. ... Losartan significantly lowered ambulatory diastolic blood pressure (losartan -5.3 mm Hg, P:<0.001 ...) after 6 weeks of therapy. Indomethacin significantly attenuated the 24-hour ambulatory diastolic blood pressure for ... losartan (2.2 mm Hg, P:<0.05) ... Changes in daytime diastolic blood pressure (7:00 AM to 11:00 PM) were similar to the 24-hour response in both groups. Nighttime diastolic blood pressure (11:01 PM to 6:59 AM) ... with losartan was unaffected (0.4 mm Hg). Thus, concurrent treatment with indomethacin similarly attenuates the 24-hour antihypertensive response to losartan ... /Salt not specified/
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 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 losartan and an NSAIA, including selective COX-2 inhibitors.
Decreased plasma concentrations of losartan and its active metabolite observed when losartan potassium is used concomitantly with rifampin.
For more Interactions (Complete) data for Losartan (20 total), please visit the HSDB record page.

[1]. Angiotensin II type 1 receptor blockers. Circulation, 2001. 103(6): p. 904-12.

[2]. Evidence for expression and function of angiotensin II receptor type 1 in pulmonary epithelial cells. Respir Physiol Neurobiol, 2014.

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[3]. Angiotensin II type I receptor and miR-155 in endometrial cancers: synergistic antiproliferative effects of anti-miR-155 and losartan on endometrial cancer cells. Gynecol Oncol, 2012. 126(1): p. 124-31.

[4]. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science, 2006. 312(5770): p. 117-21.

[5]. Effects of losartan on angiotensin and bradykinin peptides and angiotensin-converting enzyme. J Cardiovasc Pharmacol, 1995. 26(2): p. 233-40.

Therapeutic Uses
Angiotensin II Type 1 Receptor Blockers; Anti-Arrhythmia Agents; Antihypertensive Agents
Cozarr is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents, including diuretics. /Included in US product label/
Cozarr is indicated to reduce the risk of stroke in patients with hypertension and left ventricular hypertrophy, but there is evidence that this benefit does not apply to Black patients. /Included in US product label/
Cozaar is indicated for the treatment of diabetic nephropathy with an elevated serum creatinine and proteinuria (urinary albumin to creatinine ratio =300 mg/g) in patients with type 2 diabetes and a history of hypertension. In this population, Cozaar reduces the rate of progression of nephropathy as measured by the occurrence of doubling of serum creatinine or end stage renal disease (need for dialysis or renal transplantation). /Included in US product label/
For more Therapeutic Uses (Complete) data for Losartan (6 total), please visit the HSDB record page.

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Drug Warnings
/BOXED WARNING/ WARNING: FETAL TOXICITY. When pregnancy is detected, discontinue Cozaar 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 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 Cozaar as soon as possible. These adverse outcomes are usually associated with the 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 renin-angiotensin 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 Cozaar, unless it is considered life-saving 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 Cozaar 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 Losartan (21 total), please visit the HSDB record page.

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Pharmacodynamics
Losartan is an angiotensin II receptor blocker used to treat hypertension, diabetic nephropathy, and to reduce the risk of stroke. Losartan has a long duration of action as it is given once daily. Patients taking losartan should be regularly monitored for hypotension, renal function, and potassium levels.

C22H23CLN6O

422.91

422.162

C, 62.48; H, 5.48; Cl, 8.38; N, 19.87; O, 3.78

114798-26-4

Losartan Carboxylic Acid; 124750-92-1; Losartan-d4 (carboxylic acid); 1246820-62-1; Losartan potassium; 124750-99-8; Losartan-d4; 1030937-27-9; Losartan-d3 Carboxylic Acid; 1189729-40-5; Losartan-d2; 1030936-22-1; Losartan-d9; 1030937-18-8

3961

White to light yellow solid powder

1.4±0.1 g/cm3

682.0±65.0 °C at 760 mmHg

183-184ºC

366.3±34.3 °C

0.0±2.2 mmHg at 25°C

1.681

3.57

92.51

2

5

8

30

520

0

ClC1=C(C([H])([H])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])C([H])([H])[H])=N1

PSIFNNKUMBGKDQ-UHFFFAOYSA-N

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)

[2-butyl-5-chloro-3-[[4-[2-(2H-tetrazol-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol

DUP 89; DUP-89; DUP89

2934.99.03.00

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)

DMSO: ≥ 100 mg/mL (~236.5 mM)

配方 1 中的溶解度: ≥ 2.08 mg/mL (4.92 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 20.8 mg/mL澄清DMSO储备液加入400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.08 mg/mL (4.92 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
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