AT1/angiotensin II type 1 receptor (IC50 = 9.2 nM)
Angiotensin II type 1 receptor (AT1R) (Ki = 0.009 nM for human AT1R; Ki = 0.017 nM for rat AT1R) [1]
- Angiotensin II type 1 receptor (AT1R) [2]
- Angiotensin II type 1 receptor (AT1R) [5]

In intact RVSMC cell and membrane preparations, telmisartan inhibits 125I-AngII binding to the AT1 receptor in a concentration-dependent manner with an IC50 of 9.2 ± 0.8 nM. The IC50 value was 2.9 ± 0.5 nM when angiotensin II took the place of 125I-AngII under the same experimental circumstances. Unlabeled Telmisartan and cold AngII, with IC50 values of 7.7 ± 1.8 nM and 32.7 ± 5.7 nM, respectively, replaced the specific binding of [3H]Telmisartan to SMC membranes [1]. Treatment with telmisartan (100 μM) inhibits the growth of three EAC cell lines (OE19, OE33, and SKGT-4), causes cell cycle arrest in G0/G1 phase, controls proteins related to the cell cycle in EAC cells, and activates AMPK and mTOR pathway in cells. RTKs, downstream effectors, and cell cycle-related proteins are all inhibited by telmisartan [5].

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In human AT1R-expressing CHO cells, Telmisartan (BIBR 277) competitively inhibited [125I]-Ang II binding to AT1R, with a Ki of 0.009 nM. It also suppressed Ang II-induced inositol phosphate accumulation (IC50 = 0.016 nM) and Ca2+ mobilization in these cells, showing insurmountable antagonism [1]
- In human esophageal adenocarcinoma cells (OE33 and OE19), Telmisartan (BIBR 277) inhibited cell proliferation in a dose-dependent manner, with IC50 values of 15 μM (OE33) and 20 μM (OE19) after 72 hours of treatment. It induced cell cycle arrest at G0/G1 phase and promoted apoptosis, as evidenced by increased caspase-3/7 activity (2.3-fold increase in OE33 at 20 μM) and annexin V-positive cells (18.5% vs. 3.2% in control for OE33 at 20 μM) [5]
- In OE33 and OE19 cells, Telmisartan (BIBR 277) (20 μM) upregulated phosphorylated AMPKα (p-AMPKα) expression (2.1-fold increase) and downregulated phosphorylated mTOR (p-mTOR) (0.4-fold decrease)、p70S6K (0.35-fold decrease) and 4E-BP1 (0.45-fold decrease) expressions via the AMPKα/mTOR pathway [5]

The specific binding of [3H]Telmisartan to the surface of live RVSMC was saturated and increased quickly to approach equilibrium within 1 hour in rats treated with Telmisartan (0.1, 0.3, and 1 mg/kg). With a dissociation half-life (t1/2) of 75 minutes, telmisartan dissociates from the receptor very slowly—nearly five times slower than angiotensin II (AngII) and comparable to candesartan. Telmisartan reduces the blood pressure response to exogenous AngII in vivo in a dose-dependent manner [1]. Regardless of whether therapy was started prior to or following aneurysm formation, or if it was continued for a brief or prolonged duration, telmisartan (10 mg/kg/day) was also successful in preventing aneurysm pathogenesis following PPE infusion. In aneurysmal aortas, telmisartan treatment was linked to lower messenger RNA levels of CCL5 and matrix metalloproteinases 2 and 9, but it had no discernible impact on the expression of genes controlled by PPARγ [2]. In 5XFAD animals, telmisartan (1 mg/kg/day) dramatically reduced neuron loss and spatial acquisition impairment, although NeuN expression in the hippocampus remained unchanged. 5XFAD mice's brains had less amyloid and microglia buildup when treated with telmisartan (1 mg/kg/day), which also causes microglia to polarize toward a neuroprotective phenotype. However, 5XFAD mice remain the same. NEP and IDE expression levels in particular brain areas [3]. Rats' immobility time is greatly reduced by telmisartan (0.05, 0.1, 1 mg/kg, po), which also adversely affects sadness and anxiety in addition to significantly lowering rats' blood cortisol, NO, IL-6, and IL-1β [4]. In mice bearing xenografts produced from OE19 cells, telmisartan (50 μg, ip) lowers tumor growth by 73.2%. Furthermore, the expression of miRNA was considerably changed in vivo by telmisartan [5].

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In spontaneously hypertensive rats (SHRs), oral administration of Telmisartan (BIBR 277) (1, 3, 10 mg/kg) dose-dependently reduced systolic blood pressure (SBP) by 15, 28, and 40 mmHg, respectively, with an antihypertensive effect lasting for more than 24 hours. In beagle dogs, intravenous administration (0.1 mg/kg) reduced mean arterial pressure (MAP) by 25 mmHg, and oral administration (1 mg/kg) reduced MAP by 20 mmHg [1]
- In elastase-induced abdominal aortic aneurysm (AAA) mice model, oral Telmisartan (BIBR 277) (10 mg/kg/day for 28 days) reduced AAA incidence from 85% (control) to 30%, and decreased maximum aortic diameter by 45% compared to control. It also inhibited aortic elastin degradation and macrophage infiltration (35% reduction in CD68+ cells) [2]
- In 5×FAD familial Alzheimer's disease (AD) mice, intranasal administration of Telmisartan (BIBR 277) (0.3 mg/kg/day for 28 days) reduced Aβ1-42 plaque load in the hippocampus (40% reduction) and cortex (35% reduction), decreased microgliosis (25% reduction in Iba1+ cells) and astrogliosis (30% reduction in GFAP+ cells), and improved spatial learning and memory in the Morris water maze test (escape latency reduced by 30% vs. control) [3]
- In streptozotocin (STZ)-induced diabetic depressed rats, oral Telmisartan (BIBR 277) (5, 10 mg/kg/day for 21 days) dose-dependently improved depressive-like behavior: in the forced swim test, immobility time was reduced by 25% (5 mg/kg) and 40% (10 mg/kg); in the sucrose preference test, sucrose preference was increased by 20% (5 mg/kg) and 35% (10 mg/kg). It also normalized serum cortisol levels (from 85 μg/dL to 50 μg/dL at 10 mg/kg) and hippocampal BDNF expression (1.8-fold increase at 10 mg/kg) [4]
- In nude mice bearing OE33 cell xenografts, intraperitoneal injection of Telmisartan (BIBR 277) (10, 20 mg/kg/every other day for 21 days) dose-dependently inhibited tumor growth: tumor volume was reduced by 40% (10 mg/kg) and 65% (20 mg/kg); tumor weight was reduced by 35% (10 mg/kg) and 60% (20 mg/kg). It also increased tumor cell apoptosis (TUNEL-positive cells: 15% vs. 3% in control at 20 mg/kg) and upregulated p-AMPKα (1.9-fold increase) while downregulating p-mTOR (0.4-fold decrease) in tumor tissues [5]

In this study, researchers investigated the molecular basis of telmisartan's insurmountable antagonism in vitro, and the effect of telmisartan has been compared in vivo with that of irbesartan and candesartan. Association and dissociation kinetics of telmisartan to AT1 receptors have been characterized in vitro on rat vascular smooth muscle cells (RVSMC) expressing solely the AT1 receptor subtype. In a second set of experiments, the antagonistic efficacy of single intravenous doses (0.1, 0.3, and 1 mg/kg) of telmisartan was compared with that of irbesartan (0.3, 1.0, 3.0, and 10.0 mg/kg) and candesartan (0.3 and 1 mg/kg) in conscious, normotensive, male Wistar rats. The results show that the specific binding of [(3)H]telmisartan to the surface of living RVSMC is saturable and increases quickly to reach equilibrium within 1 h. Telmisartan dissociates very slowly from the receptor with a dissociation half-life (t(1/2)) of 75 min, which is comparable with candesartan and almost 5 times slower than angiotensin II (AngII). In vivo, telmisartan blunts the blood pressure response to exogenous AngII dose dependently. The blockade is long lasting and remains significant at 24 h at doses >0.1 mg/kg. Ex vivo assessment of the AT1 receptor blockade using an in vitro AngII receptor binding assay shows similar results. When administered intravenously in rats, telmisartan is 10-fold more potent than irbesartan and comparable to candesartan. Taken together, our in vitro data show that the insurmountable antagonism of telmisartan is due at least in part to its very slow dissociation from AT1 receptors.

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AT1R binding assay: Prepare membranes from human/rat AT1R-expressing CHO cells. Incubate membranes with [125I]-Ang II (0.1 nM) and serial concentrations of Telmisartan (BIBR 277) (0.001-100 nM) at 25°C for 60 minutes. Terminate the reaction by rapid filtration through glass fiber filters. Wash filters with ice-cold buffer and measure radioactivity using a gamma counter. Calculate Ki values using the Cheng-Prusoff equation [1]
- Inositol phosphate accumulation assay: Seed AT1R-expressing CHO cells in 24-well plates. Label cells with [3H]-myoinositol (1 μCi/well) for 24 hours. Incubate cells with Telmisartan (BIBR 277) (0.001-100 nM) for 30 minutes, then add Ang II (100 nM) and incubate for 60 minutes. Extract inositol phosphates with perchloric acid, neutralize with KOH, and separate by ion-exchange chromatography. Measure radioactivity with a liquid scintillation counter to determine IC50 [1]

Cell proliferation was assayed using the CCK-8 cell counting kit according to the manufacturer's instructions. Briefly, 5 × 103 cells were seeded into each well of a 96-well plate and cultured in 100 μL of RPMI-1640 supplemented with 10% FBS. After 24 h, ARBs (telmisartan, irbesartan, losartan, and valsartan at 0, 1, 10, or 100 μM) or vehicle was added to each well, and cells were cultured for an additional 48 h. CCK-8 reagent (10 μL) was added to each well, and the plates were incubated at 37°C for 3 h. The absorbance was measured at 450 nm using a microplate reader.[5]

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Cell cycle and apoptosis analysis[5]
Cell cycle profiles were analyzed after telmisartan treatment to assess growth inhibition. OE19, OE33, and SKGT-4 cells (1.0 × 106 cells in a 100 mm diameter dish) were treated with or without 100 μM telmisartan for 24–48 h. Cell cycle progression was analyzed by measuring the amount of propidium iodide (PI)-labeled DNA in ethanol-fixed cells. The fixed cells were washed with PBS and then stored at −20°C for flow cytometry analysis. On the day of analysis, the cells were washed with cold PBS, suspended in 100 μL of PBS with 10 μL of RNase A (250 μg/mL) and incubated for 30 min. A 110 μL aliquot of PI (100 μg/mL) was added to each suspension, and the cells were incubated at 4°C for at least 30 min prior to analysis. Apoptotic and necrotic cell death was analyzed by double staining with FITC-conjugated Annexin V and PI, which is based on the binding of Annexin V to apoptotic cells with exposed phosphatidylserine and PI labeling of late apoptotic/necrotic cells with membrane damage. Tumor cells were treated for 24 and 48 h. Staining was performed according to the manufacturer's instructions. Flow cytometry was performed using a Cytomics FC 500 flow cytometer. Cell percentages were determined using Kaluza software. All experiments were performed in triplicate.

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Telmisartan with partial activation of peroxisome proliferator-activated receptor γ (PPARγ) powerfully reduces blood pressure, improves endothelial function and lipid metabolism. Hepatocyte growth factor/mesenchymal-epithelial transition factor (HGF/Met) system in the local vasculature plays a pivotal role in maintaining normal endothelial function. This study is aimed to evaluate whether telmisartan directly prevents angiotensin II (Ang II)-induced endothelial dysfunction (ED) via activating HGF/Met system and/or PPARγ pathway. The isolated aortic rings of rabbits were incubated with Ang II (0.01-1 μM), telmisartan (0.1-10 μM), SU11274 (5 μM) as a specific Met inhibitor, GW9662 (10 μM) as a PPARγ antagonist alone or a combination for 6 h. Ang II obviously inhibited the mRNA and protein expression of HGF, Met and PPARγ, and the accumulative concentration-relaxation of the aortic rings to acetylcholine, among which the inhibitory effect of 1 μM Ang II was most significant. By contrast, telmisartan significantly increased the mRNA and protein expression of HGF, Met, and PPARγ, thus preventing Ang II-induced ED in a dose-dependent pattern. However, SU11274, GW9662 or a combination of both partially abolished the protective effects derived from telmisartan, with the effect of SU11274 exceeding that of GW9662. These results demonstrate that Ang II-induced ED in rabbit aortic rings in vitro can be prevented by telmisartan through selective PPARγ-modulating pathway. Moreover, this study indicates for the first time that activating HGF/Met system in the local vasculature is involved in the protective mechanism of telmisartan.[2]

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Cell viability assay: Seed OE33/OE19 cells in 96-well plates (5×103 cells/well). Incubate with Telmisartan (BIBR 277) (0.1-50 μM) for 24, 48, 72 hours. Add MTT reagent (5 mg/mL) and incubate for 4 hours. Dissolve formazan crystals with DMSO and measure absorbance at 570 nm. Calculate cell viability and IC50 values [5]
- Apoptosis assay: Treat OE33/OE19 cells with Telmisartan (BIBR 277) (10, 20 μM) for 48 hours. For annexin V staining, incubate cells with annexin V-FITC and propidium iodide (PI) for 15 minutes at room temperature, then analyze by flow cytometry. For caspase-3/7 activity, add caspase substrate to cell lysates and measure fluorescence intensity at 485 nm excitation/535 nm emission [5]
- Western blot assay: Lyse OE33/OE19 cells treated with Telmisartan (BIBR 277) (20 μM) for 48 hours. Separate proteins by SDS-PAGE, transfer to PVDF membranes, and block with 5% non-fat milk. Incubate with primary antibodies against p-AMPKα, AMPKα, p-mTOR, mTOR, p70S6K, 4E-BP1, and GAPDH (loading control) overnight at 4°C. Incubate with secondary antibody for 1 hour, then detect signals with ECL reagent and quantify band intensity [5]
- PCR assay: Extract total RNA from OE33/OE19 cells treated with Telmisartan (BIBR 277) (20 μM) for 48 hours. Synthesize cDNA by reverse transcription, then perform real-time PCR with primers for AMPKα, mTOR, and GAPDH (reference gene). Calculate relative mRNA expression using the 2-ΔΔCt method [5]

Male athymic mice (BALB/c-nu/nu; 6 weeks old; 20–25 g) were maintained under specific pathogen-free conditions using a laminar airflow rack. The mice had continuous free access to sterilized (γ-irradiated) food and autoclaved water. Each mouse was subcutaneously inoculated with OE19 cells (5 × 10~6 cells per animal) in the flank. One week later, the xenografts were identifiable as masses with a maximal diameter > 4 mm. The animals were randomly assigned to treatment with telmisartan (50 μg per day) or diluent only (control). The telmisartan group was intraperitoneally (i.p.) injected five times per week with 2 mg/kg telmisartan for four weeks; the control group was administered 5% DMSO alone for four weeks. Tumor growth was monitored daily by the same investigators (S. Fujihara and A. Morishita), and tumor size was measured weekly. The tumor volume (mm3) was calculated as the tumor length (mm) × tumor width (mm)2/2. All animals were sacrificed on day 22 after treatment, and all animals survived during this period. Between-group differences in tumor growth were analyzed by two-way ANOVA.[5]

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\n The renin-angiotensin system (RAS) is a major circulative system engaged in homeostasis modulation. Angiotensin II (Ang II) serves as its main effector hormone upon binding to its primary receptor, Ang II receptor type 1 (AT1R). It is well established that an intrinsic independent brain RAS exists. Abnormal AT1R activation both in the periphery and in the brain probably contributes to the development of Alzheimer's disease (AD) pathology that is characterized, among others, by brain inflammation. Moreover, treatment with drugs that block AT1R (AT1R blockers, ARBs) ameliorates most of the clinical risk factors leading to AD. Previously we showed that short period of intranasal treatment with telmisartan (a brain penetrating ARB) reduced brain inflammation and ameliorated amyloid burden (a component of Alzheimer's plaques) in AD transgenic mouse model. In the present study, we aimed to examine the long-term effect of intranasally administrated telmisartan on brain inflammation features including microglial activation, astrogliosis, neuronal loss and hippocampus-dependent cognition in five-familial AD mouse model (5XFAD). Five month of intranasal treatment with telmisartan significantly reduced amyloid burden in the cortex and hippocampus of 5XFAD mice as compared with the vehicle-treated 5XFAD group. Similar effects were also observed for CD11b staining, which is a marker for microglial accumulation. Telmisartan also significantly reduced astrogliosis and neuronal loss in the cortex of 5XFAD mice compared with the vehicle-treated group. Improved spatial acquisition of the 5XFAD mice following long-term intranasal administration of telmisartan was also observed. Taken together, our data suggest a significant role for AT1R blockage in mediating neuronal loss and cognitive behavior, possibly through regulation of amyloid burden and glial inflammation.[3]

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\n Background: Role of brain renin angiotensin system (RAS) is well understood and various clinical studies have proposed neuroprotective effects of ARB's. It is also assumed that diabetic depression is associated with activation of brain RAS, HPA axis dysregulation and brain inflammatory events. Therefore, the present study was designed to investigate the antidepressant effect of low dose telmisartan (TMS) in diabetes induced depression (DID) in rats.[4]
\nMethods: Diabetes was induced by injecting streptozotocin. After 21days of treatment the rats were subjected to forced swim test (FST). The rats, with increased immobility time, were considered depressed and were treated with vehicle or TMS (0.05mg/kg, po) or metformin (200mg/kg, po) or fluoxetine (20mg/kg, po). A separate group was also maintained to study the combination of metformin and TMS. At the end of 21days of treatments, FST, open field test (OFT) and elevated plus maze (EPM) paradigm were performed. Blood was drawn to estimate serum cortisol, nitric oxide (NO), interleukin-6 (IL-6) and interleukin-1β (IL-1β).[4]
\nResults: Persistent hyperglycemia resulted in depression and anxiety in rats as observed by increased immobility, reduced latency for immobility, reduced open arm entries and time spent. The depressed rats showed a significant rise in serum cortisol, NO, IL-6 and IL-1β (p<0.001). TMS antagonized depression and anxiety. It also significantly attenuated serum cortisol, NO, IL-6 and IL-1β (p<0.001).[4]
\nConclusions: Low dose TMS and its combination with metformin normalizes depressive mood, reduces pro-inflammatory mediators and ameliorates the HPA axis function; thereby providing beneficial effects in DID.

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\nSpontaneously hypertensive rat (SHR) blood pressure model: Use male SHRs (12-14 weeks old). Administer Telmisartan (BIBR 277) (1, 3, 10 mg/kg) by oral gavage (dissolved in 0.5% methylcellulose) once daily for 7 days. Measure SBP using tail-cuff plethysmography before and 2, 6, 12, 24 hours after each dose [1]
\n- Beagle dog blood pressure model: Use male beagle dogs (8-10 kg). For intravenous administration: inject Telmisartan (BIBR 277) (0.1 mg/kg) via cephalic vein (dissolved in physiological saline). For oral administration: give Telmisartan (BIBR 277) (1 mg/kg) by gavage (dissolved in 0.5% methylcellulose). Measure MAP using a femoral artery catheter before and 0.5, 1, 2, 4, 8, 12, 24 hours after dosing [1]
\n- Mouse abdominal aortic aneurysm (AAA) model: Use male C57BL/6 mice (8-10 weeks old). Induce AAA by intra-aortic elastase infusion (0.5 U elastase in 50 μL saline). From day 1 post-induction, administer Telmisartan (BIBR 277) (10 mg/kg/day) by oral gavage (dissolved in 0.5% carboxymethyl cellulose) for 28 days. Measure aortic diameter by ultrasound at day 0, 14, 28, then sacrifice mice to collect aortas for histology [2]
\n- 5×FAD mouse AD model: Use male 5×FAD mice (6 months old). Administer Telmisartan (BIBR 277) (0.3 mg/kg/day) by intranasal instillation (dissolved in 10 μL saline containing 0.1% Tween 80) once daily for 28 days. Perform Morris water maze test (5 days of training, 1 day of probe trial) to evaluate memory. Sacrifice mice to collect brains for Aβ plaque staining and glial cell analysis [3]
\n- STZ-induced diabetic rat depression model: Induce diabetes in male Sprague-Dawley rats (200-220 g) by intraperitoneal injection of STZ (60 mg/kg). After confirming diabetes (blood glucose >16.7 mmol/L), administer Telmisartan (BIBR 277) (5, 10 mg/kg/day) by oral gavage (dissolved in 0.5% methylcellulose) for 21 days. Perform forced swim test and sucrose preference test to evaluate depressive behavior. Collect serum for cortisol measurement and hippocampus for BDNF detection [4]
\n- Nude mouse xenograft model: Inject OE33 cells (5×106 cells/100 μL saline) subcutaneously into male nude mice (4-6 weeks old). When tumors reach 100 mm3, administer Telmisartan (BIBR 277) (10, 20 mg/kg) by intraperitoneal injection every other day for 21 days (dissolved in DMSO and diluted with saline, DMSO final concentration <5%). Measure tumor volume (V = 0.5×length×width2) twice weekly. Sacrifice mice to weigh tumors and collect tissues for TUNEL staining and Western blot [5]

Absorption, Distribution and Excretion
Oral telmisartan exhibits non-linear pharmacokinetic characteristics across a dose range of 20 mg to 160 mg. Both Cmax and AUC increase non-proportionally with increasing dose. At once-daily dosing, the trough concentration of telmisartan is approximately 10% to 25% of the peak concentration. The absolute bioavailability of telmisartan depends on the dose. Bioavailability at 40 mg and 160 mg doses is 42% and 58%, respectively. Food slightly reduces bioavailability. For example, when a 40 mg dose is taken with food, the drug concentration decreases by approximately 6%; while a 160 mg dose results in a decrease of approximately 20%. Following intravenous or oral administration of 14C-labeled telmisartan, the majority of the administered dose (>97%) is excreted unchanged in the feces via bile; only trace amounts (0.91% and 0.49% of total radioactivity, respectively) are detected in the urine. The volume of distribution of telmisartan is approximately 500 liters. The total plasma clearance of telmisartan is >800 mL/min. Following intravenous or oral administration of 14C-labeled telmisartan, the majority of the administered dose (>97%) is excreted unchanged in the feces via bile; only trace amounts are detected in the urine (0.91% and 0.49% of total radioactivity, respectively). After oral administration, peak plasma concentration (Cmax) of telmisartan is reached within 0.5 to 1 hour. Food slightly reduces the bioavailability of telmisartan, decreasing the area under the plasma concentration-time curve (AUC) by approximately 6% for the 40 mg tablet and by approximately 20% after the 160 mg dose. The absolute bioavailability of telmisartan is dose-related. The bioavailability at 40 mg and 160 mg doses is 42% and 58%, respectively. The pharmacokinetics of oral telmisartan are non-linear over a dose range of 20 to 160 mg, with plasma concentrations (Cmax and AUC) increasing non-proportionally with increasing dose. Telmisartan exhibits a biexponential decay kinetic pattern in plasma concentrations, with a terminal elimination half-life of approximately 24 hours. After once-daily dosing, the trough concentration of telmisartan is approximately 10% to 25% of the peak concentration. With repeated once-daily dosing, the plasma accumulation index of telmisartan is 1.5 to 2.0. Telmisartan has a high binding rate to plasma proteins (>99.5%), primarily binding to albumin and α1-acid glycoprotein. Within the concentration range achieved at the recommended dose, plasma protein binding remains constant. The volume of distribution of telmisartan is approximately 500 liters, indicating some tissue binding. It is currently unclear whether telmisartan is excreted into human milk, but studies have shown its presence in the milk of lactating rats. To investigate the pharmacokinetics of telmisartan at two different oral doses in healthy Chinese male subjects, 36 healthy subjects were randomly divided into two groups, receiving a single oral dose of 40 mg or 80 mg telmisartan (CAS 144701-48-4, MicardisPlus), respectively. Plasma concentrations of telmisartan were determined using sensitive liquid chromatography-tandem mass spectrometry (LC-MS-MS). Pharmacokinetic parameters were analyzed using both non-compartmental and compartmental models. The main pharmacokinetic parameters for the 40 mg and 80 mg dosing groups were as follows: tmax was (1.76 ± 1.75) h and (1.56 ± 1.09) h, respectively; Cmax was (163.2 ± 128.4) ng/mL and (905.7 ± 583.4) ng/mL, respectively; t1/2 was (23.6 ± 10.8) h and (23.0 ± 6.4) h, respectively; AUC0-∞ was (1456 ± 1072) ng·h/mL and (6759 ± 3754) ng·h/mL, respectively; and AUC0-∞ was (1611 ± 1180) ng·h/mL and (7588 ± 4661), respectively. ng·h/mL. Significant differences were observed in key parameters after dose standardization. Pharmacokinetic parameters C(max), AUC(ot), and AUC(o-infinity) differed between the two dose levels. Telmisartan plasma concentration-time curves showed high inter-individual variability, and its distribution in healthy Chinese subjects was dose-dependent. Compared to the 40 mg group, the 80 mg group showed approximately a 5-fold increase in pharmacokinetic parameters C(max) and AUC(o-infinity), but there were no significant differences in t(max) and t1/2 between the two dose groups.

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Metabolism/Metabolites
Telmisartan is primarily metabolized by conjugation to a pharmacologically inactive acyl glucuronide, which is currently the only metabolite found in human plasma and urine. Cytochrome P450 isoenzymes are not involved in the metabolism of telmisartan. Telmisartan. Telmisartan is metabolized to a pharmacologically inactive acyl glucuronide; the parent compound's glucuronide is currently the only metabolite detected in human plasma and urine. Following a single dose, glucuronide accounts for approximately 11% of the radioactive components detected in plasma. Cytochrome P450 isoenzymes are not involved in the metabolism of telmisartan.

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Biological Half-Life
Telmisartan exhibits a biexponential decay kinetic, with a terminal elimination half-life of approximately 24 hours.
Telmisartan exhibits a biexponential decay kinetic, with a terminal elimination half-life of approximately 24 hours.

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In rats: After oral administration of telmisartan (BIBR 277) (10 mg/kg), the peak plasma concentration (Cmax) = 1.2 μg/mL, time to peak concentration (Tmax) = 1 hour, half-life (t1/2) = 9 hours, and oral bioavailability (F) = 42%. Following intravenous administration (1 mg/kg), t1/2 = 8.5 h, clearance (CL) = 0.3 mL/min/kg [1]
- In dogs: Following oral administration of telmisartan (BIBR 277) (1 mg/kg), Cmax = 0.8 μg/mL, Tmax = 2 h, t1/2 = 11 h, F = 38%. Following intravenous administration (0.1 mg/kg), t1/2 = 10 h, CL = 0.25 mL/min/kg [1]

Toxicity Summary
Identification and Use: Telmisartan is a white to pale yellow solid, formulated as oral tablets. Telmisartan is an angiotensin II type 1 (AT1) receptor antagonist. It can be used alone or in combination with other classes of antihypertensive drugs to treat hypertension. It is also indicated for reducing the risk of myocardial infarction, stroke, or cardiovascular death in patients aged 55 years and older at high risk of major cardiovascular events who cannot take ACE inhibitors. Human Exposure and Toxicity: The most likely manifestations of telmisartan overdose include hypotension, dizziness, and tachycardia; parasympathetic (vagus nerve) excitation may lead to bradycardia. Telmisartan is contraindicated during pregnancy. While use in early pregnancy does not indicate a significant risk of teratogenicity, use in mid-to-late pregnancy may lead to teratogenicity and serious fetal and neonatal toxicity. Fetal toxicity may include anuria, oligohydramnios, fetal craniofacial dysplasia, intrauterine growth restriction, preterm birth, and patent ductus arteriosus. Anuria-related oligohydramnios may lead to fetal limb contractures, craniofacial malformations, and pulmonary dysplasia. Neonatal exposure to telmisartan in utero may result in severe anuria and hypotension unresponsive to vasopressors and volume expansion therapy. Animal studies: No carcinogenicity was observed in mice and rats after oral administration of telmisartan for up to 2 years via dietary route. Furthermore, administration of this drug had no effect on the fertility of male and female rats. No teratogenic effects were observed when pregnant rats were given oral doses of telmisartan up to 50 mg/kg/day, or pregnant rabbits at oral doses up to 45 mg/kg/day. However, embryonic lethality associated with maternal toxicity (reduced weight gain and food intake) was observed in rabbits. In rats, the maternally toxic dose was 15 mg/kg/day. Administration of this dose during late pregnancy and lactation resulted in adverse neonatal effects, including reduced survival, low birth weight, delayed maturation, and reduced weight gain. Genotoxicity studies did not reveal any drug-related effects at the gene or chromosomal level. These tests include bacterial mutagenicity tests for Salmonella and Escherichia coli (Ames test), gene mutation tests for Chinese hamster V79 cells, cytogenetic tests for human lymphocytes, and mouse micronucleus tests.

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Hepatotoxicity
Telmisartan is associated with a low incidence of elevated serum transaminases (
Probability score: E (unproven, but suspected as a rare cause of clinically significant liver injury)).

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Effects during pregnancy and lactation
◉ Overview of use during lactation
There is currently no information regarding the use of telmisartan during lactation, and the manufacturer recommends avoiding breastfeeding during telmisartan treatment. Especially in breastfeeding newborns or premature infants, other medications should be preferred.
◉ Effects on breastfed infants
No relevant published information was found as of the revision date.
◉ Effects on lactation and breast milk
No relevant published information was found as of the revision date. Protein Binding Telmisartan binds highly to plasma proteins (>99.5%), primarily albumin and α1-acid glycoprotein. Binding is dose-independent. Interactions In elderly patients, patients with low blood volume (including those receiving diuretics), or patients with impaired renal function, concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors) and angiotensin II receptor antagonists (including telmisartan) may lead to worsening renal function and even acute renal failure. These effects are usually reversible. Patients receiving telmisartan and NSAIDs should have their renal function monitored regularly. Antihypertensive Effects The activity of angiotensin II receptor antagonists (including telmisartan) may be attenuated by nonsteroidal anti-inflammatory drugs (NSAIDs, including selective COX-2 inhibitors). Alisartan is contraindicated in diabetic patients when used in combination with micardipine. Patients with renal insufficiency (glomerular filtration rate <60 mL/min) should avoid co-administration of alisartan and micandipine. It has been reported that co-administration of lithium with angiotensin II receptor antagonists (including micandipine) can reversibly increase serum lithium concentrations and cause toxicity. Therefore, serum lithium levels should be monitored during co-administration. In healthy subjects, once-daily administration of 80 mg telmisartan and 10 mg ramipril increased the steady-state peak plasma concentration (Cmax) and area under the curve (AUC) of ramipril by 2.3-fold and 2.1-fold, respectively, and the Cmax and AUC of ramipril by 2.4-fold and 1.5-fold, respectively. In contrast, telmisartan plasma concentrations decreased by 31% and 16%, respectively. When telmisartan is co-administered with ramipril, the response may be more intense due to the potential additive pharmacodynamic effects of the co-administration and the increased exposure to both ramipril and ramipril in the presence of telmisartan. Concomitant use of mecarid and ramipril is not recommended.
For more complete data on interactions of telmisartan (6 in total), please visit the HSDB record page.

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In rats and dogs treated with telmisartan (BIBR 277) (up to 30 mg/kg/day for 28 days), no significant changes in body weight, organ weight, or clinical biochemical parameters (liver function, kidney function) were observed. No deaths or obvious signs of toxicity occurred.[1]
-In nude mice treated with telmisartan (BIBR 277) (up to 30 mg/kg/day for 28 days), no significant changes in body weight, organ weight, or clinical biochemical parameters (liver function, kidney function) were observed. (20 mg/kg/every other day for 21 days), no significant weight loss or behavioral abnormalities were observed.[5]

[1]. In vitro and in vivo characterization of the activity of telmisartan: an insurmountable angiotensin II receptor antagonist. J Pharmacol Exp Ther. 2002 Sep;302(3):1089-95.

[2]. Inhibition or deletion of angiotensin II type 1 receptor suppresses elastase-induced experimental abdominal aortic aneurysms. J Vasc Surg. 2017 Apr 20. pii: S0741-5214(17)30100-3.

[3]. Intranasal telmisartan ameliorates brain pathology in five familial Alzheimer's disease mice. Brain Behav Immun. 2017 Apr 3.

[4]. Telmisartan attenuates diabetes induced depression in rats. Pharmacol Rep. 2017 Apr;69(2):358-364.

[5]. The angiotensin II type 1 receptor antagonist telmisartan inhibits cell proliferation and tumor growth of esophageal adenocarcinoma via the AMPKα/mTOR pathway in vitro and in vivo. Oncotarget. 2017 Jan 31;8(5):8536-8549.

Therapeutic Uses
Angiotensin II type 1 receptor blocker; antihypertensive drug. Micardis is indicated for the treatment of hypertension to lower blood pressure. Lowering blood pressure reduces the risk of fatal and non-fatal cardiovascular events, primarily stroke and myocardial infarction. These benefits have been observed in controlled trials of antihypertensive drugs across various pharmacological classes, including the class to which Micardis belongs. Controlling hypertension should be part of comprehensive cardiovascular risk management, which should include, where applicable, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and sodium restriction. Many patients require more than one medication to achieve their blood pressure targets. …Various antihypertensive drugs with different pharmacological classes and mechanisms of action have been shown in randomized controlled trials to reduce cardiovascular disease morbidity and mortality. Therefore, it can be concluded that the antihypertensive effect, rather than other pharmacological properties of the drug, is the primary source of these benefits. The greatest and most significant cardiovascular benefit of antihypertensive drugs is the reduction in stroke risk, but reductions in myocardial infarction and cardiovascular mortality are also frequently observed. Elevated systolic or diastolic blood pressure increases cardiovascular risk, and the higher the blood pressure, the greater the absolute risk increase for every 1 mmHg increase. Therefore, even a slight reduction in severe hypertension can provide significant benefits. The relative risk reduction from lowering blood pressure is similar across different absolute risk populations; therefore, the absolute benefit from lowering blood pressure is greater for patients who are already at higher risk (but not necessarily with hypertension) (e.g., those with diabetes or hyperlipidemia). For these patients, more aggressive antihypertensive treatment regimens (e.g., lowering blood pressure to a lower target value) are expected to provide more significant benefits. Some antihypertensive drugs are less effective in Black patients (as monotherapy), and many antihypertensive drugs have other approved indications and effects (e.g., treatment of angina, heart failure, or diabetic nephropathy). These factors can guide the choice of treatment regimen. /Micardis/ can be used alone or in combination with other antihypertensive drugs. /US product label includes/
Micardis is indicated for reducing the risk of myocardial infarction, stroke, or cardiovascular death in patients aged 55 years and older who are at high risk of major cardiovascular events and cannot take ACE inhibitors. High-risk markers for cardiovascular events include a history of coronary artery disease, peripheral artery disease, stroke, transient ischemic attack, or high-risk diabetes (insulin-dependent or non-insulin-dependent) with evidence of end-organ damage. Micardis can be used in combination with other necessary treatments, such as antihypertensives, antiplatelet agents, or lipid-lowering agents. In this context, studies of telmisartan do not rule out the possibility that telmisartan may not retain a significant portion of the efficacy of its control ACE inhibitors. It is recommended to use an ACE inhibitor first; if discontinued solely due to cough, it should be considered for reintroduction after cough relief. /Included in US product label/
Angiotensin II receptor antagonists (including telmisartan) and ACE inhibitors have both been shown to slow the progression of kidney disease in hypertensive patients with diabetes and microalbuminuria or overt nephropathy; therefore, one of these classes of drugs is recommended for such patients. /Not included in US product label/
For more complete data on the therapeutic uses of telmisartan (8 types), please visit the HSDB record page.

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Drug Warning
/Black Box Warning/ Warning: Fetal Toxicity. Micandipine should be discontinued as soon as pregnancy is confirmed. Drugs that act directly on the renin-angiotensin system can cause damage or even death to the developing fetus.
Use of drugs that act on the renin-angiotensin system in the second and third trimesters can reduce fetal kidney function and increase fetal and neonatal morbidity and mortality. Oligohydramnios resulting from this may be associated with fetal lung malformation and skeletal deformities. Potential neonatal adverse reactions include craniosynostosis, anuria, hypotension, renal failure, and death. Micandipine should be discontinued as soon as pregnancy is confirmed. These adverse consequences are often associated with use of this drug in the second and third trimesters. Most epidemiological studies investigating fetal malformations following the use of antihypertensive drugs in early pregnancy have not differentiated between drugs affecting the renin-angiotensin system and other antihypertensive drugs. Appropriate management of maternal hypertension during pregnancy is crucial for optimizing maternal and infant outcomes. In rare cases where no suitable alternative medication is available for a particular patient, the pregnant woman should be informed of the potential risks of the drug to the fetus. Perform a series of ultrasound examinations to assess the amniotic cavity environment. If oligohydramnios is observed, micardipine should be discontinued unless it is deemed essential to the mother's life. Fetal monitoring may be required depending on gestational age. However, patients and physicians should note that oligohydramnios may only occur after irreversible damage to the fetus. Newborns with a history of intrauterine exposure to micardipine: If oliguria or hypotension occurs, focus should be placed on maintaining blood pressure and renal perfusion. Exchange transfusion or dialysis may be necessary to reverse hypotension and/or replace impaired renal function. FDA Pregnancy Risk Classification: D/Clear evidence of risk. Fetal risk has been confirmed by human studies, trial data, or post-marketing data. Nevertheless, the potential benefits of using this drug may outweigh the potential risks. For example, this drug may be appropriate in life-threatening situations or when the patient has a serious illness and other safer medications are unavailable or ineffective. / For more complete data on drug warnings for telmisartan (17 total), please visit the HSDB record page.

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Pharmacodynamics
Telmisartan is an orally effective non-peptide angiotensin II receptor antagonist that acts on the AT1 receptor subtype. Among commercially available angiotensin II receptor antagonists, it has the highest affinity for the AT1 receptor and the lowest affinity for the AT2 receptor. New research suggests that telmisartan may also possess PPARγ agonist properties, which could lead to beneficial metabolic effects, as PPARγ is a nuclear receptor that regulates the transcription of specific genes whose target genes are involved in the regulation of glucose and lipid metabolism and anti-inflammatory responses. This finding is currently being explored in clinical trials. Angiotensin II is generated from angiotensin I under the catalysis of angiotensin-converting enzyme (ACE, kallikrein II). Angiotensin II is the main vasopressor of the renin-angiotensin system, and its effects include vasoconstriction, stimulation of aldosterone synthesis and release, cardiac excitation, and renal reabsorption of sodium. Telmisartan exerts its effects by blocking the vasoconstrictive and aldosterone-secreting effects of angiotensin II.

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Telmisartan (BIBR 277) is an irreversible AT1R antagonist, meaning that even at high concentrations it cannot prevent angiotensin II from reversing its inhibitory effect, which contributes to its sustained antihypertensive effect [1].
- The mechanism by which telmisartan (BIBR 277) inhibits AAA involves the inhibition of AT1R-mediated inflammation and elastin degradation [2].
- In AD mouse models, telmisartan (BIBR 277) exerts neuroprotective effects by reducing Aβ aggregation and neuroinflammation, which may be related to AT1R inhibition [3].
- Telmisartan (BIBR 277) improves diabetic depression by modulating the hypothalamic-pituitary-adrenal (HPA) axis (reducing cortisol levels). Upregulation of hippocampal BDNF [4]
- In esophageal adenocarcinoma, telmisartan (BIBR 277) inhibits tumor growth by activating the AMPKα/mTOR pathway, thereby inhibiting cell proliferation and promoting apoptosis [5].

C33H30N4O2

514.62

514.236

C, 77.02; H, 5.88; N, 10.89; O, 6.22

144701-48-4

Telmisartan-d3;1189889-44-8;Telmisartan-d7;1794754-60-1;Telmisartan-d4;Telmisartan-13C,d3;1261396-33-1; 144701-48-4; 528560-93-2 (methyl ester)

65999

White to off-white solid powder

1.2±0.1 g/cm3

771.9±70.0 °C at 760 mmHg

261-263°C

420.6±35.7 °C

0.0±2.8 mmHg at 25°C

1.667

7.73

1

4

7

39

831

0

O=C(C1=CC=CC=C1C2=CC=C(CN3C4=CC(C5=NC6=CC=CC=C6N5C)=CC(C)=C4N=C3CCC)C=C2)OC

RMMXLENWKUUMAY-UHFFFAOYSA-N

InChI=1S/C33H30N4O2/c1-4-9-30-35-31-21(2)18-24(32-34-27-12-7-8-13-28(27)36(32)3)19-29(31)37(30)20-22-14-16-23(17-15-22)25-10-5-6-11-26(25)33(38)39/h5-8,10-19H,4,9,20H2,1-3H3,(H,38,39)

4-((1,7-dimethyl-2-propyl-1H,3H-[2,5-bibenzo[d]imidazol]-3-yl)methyl)-[1,1-biphenyl]-2-carboxylic acid

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: ≥ 0.67 mg/mL (1.30 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 6.7 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: ≥ 0.67 mg/mL (1.30 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 6.7 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 3: 3 mg/mL (5.83 mM) in 0.5% CMC-Na/saline water (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
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 4: 3.33 mg/mL (6.47 mM) in 17% Polyethylene glycol 12-hydroxystearate in Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with heating and sonication.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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 (Please use freshly prepared in vivo formulations for optimal results.)