Trandolapril (0.02 mM, 1 mM; 3 d) increases the proportion of apoptotic cells in the K562 cell line by inhibiting cell development and inducing apoptosis [2].

By limiting renal interstitial matrix expression and myofibroblast activation, as well as lowering renal proinflammatory cytokines RANTES and TNF-α levels in mice with renal fibrosis, trunolapril (3 mg/kg/day; oral; 7 days) decreases obstructive nephropathy in mice [2]. In rats, trundialolapril (0.3 mg/kg/day; oral; 4 weeks) reduces cellular fibronectin accumulation, collagen, and arterial hypertrophy [3]. In rats, long-term antihypertensive effects of landopril (0.3 mg/kg/day; oral; 4 months) lower blood pressure [3]. When given orally, twice daily for four months, trundialapril (0.25 mg/kg) prevents atherosclerosis in rabbits with Watanabe hereditary hyperlipidemia [4].

Apoptosis analysis [2]
Cell Types: K562, KU812, U937 and HL60
Tested Concentrations: 0-2 mM
Incubation Duration: 0, 1, 2, 3 days
Experimental Results: 1 mM inhibits K562, KU812, U937, 0.02 mM inhibits HL60.

Animal/Disease Models: UUD (unilateral ureteral obstruction) model [2] in male CD-1 mice (18-22 g)
Doses: 3 mg/kg
Route of Administration: po (oral gavage); one time/day for 7 days
Experimental Results: Caused Renal interstitial matrix expression, including fibronectin, type I and type III collagen, is diminished and, surprisingly, myofibroblast activation is inhibited through α-smooth muscle actin (a-SMA) expression, which reduces RANTES (regulated activation, normal T cell expression and secretion) and TNF-α levels.

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Animal/Disease Models: SHR model (spontaneous hypertensive rats, 4 weeks old) [3]
Doses: 0.3 mg/kg
Route of Administration: po (oral gavage); one time/day for 4 weeks
Experimental Results: The collagen content in the aortic middle layer diminished, Arterial distensibility increases by approximately 80%.

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Animal/Disease Models: Watanabe hereditary hyperlipidemia rabbit (3 months old) [4]
Doses: 0.25 mg/kg
Route of Administration: po (oral gavage); twice a day; 9-month
Experimental Results: Atherosclerosis on the intimal surface Sclerosis is diminished, and the cholesterol c

Absorption, Distribution and Excretion
Absorption rate: 40-60%; extensive first-pass metabolism results in low bioavailability, only 4-14%. After oral administration of trodopril, approximately 33% of the parent drug and its metabolites are excreted in the urine, primarily as trodopril, and approximately 66% in the feces. 18 L 52 L/h [after intravenous injection of approximately 2 mg] /Milk/ Trodopril and its metabolites are distributed into rat milk. After oral administration of trodopril, approximately 33% of the parent drug and its metabolites are excreted in the urine, primarily as trodopril, and approximately 66% in the feces. The proportion of absorbed dose excreted in bile has not been determined. Within the 1-4 mg dose range, plasma concentrations (Cmax and AUC of trodopril and Cmax of trodopril) are dose-proportional, but the AUC of trodopril is slightly lower than the dose-proportional relationship. In addition to tripopril, at least seven other metabolites were identified, primarily glucuronides or deesterified products. Tridopril's serum protein binding rate is approximately 80%, and is concentration-independent. Tridopril's binding rate is concentration-dependent, ranging from 65% at 1000 ng/mL to 94% at 0.1 ng/mL, indicating that binding reaches saturation with increasing concentration. Following oral administration of tripopril, the absolute bioavailability of tripopril is approximately 10% (in its tripopril form), while that of tripopril is approximately 70%. After oral administration of tridopril on an empty stomach, peak plasma concentrations of tridopril occur at approximately 1 hour, while peak plasma concentrations of tridopril occur between 4 and 10 hours. The elimination half-life of tridopril is approximately 6 hours. At steady state, the effective half-life of tridopril is 22.5 hours. Like other ACE inhibitors, trodopril has a long terminal elimination phase, with only a small fraction of the administered drug reaching the terminal phase, likely representing its binding to ACE in plasma and tissues. Trodopril does not accumulate significantly after multiple doses. Food slows the absorption of trodopril but does not affect the AUC or Cmax of trodopril, nor does it affect the Cmax of trodopril. The volume of distribution of trodopril is approximately 18 liters. Following an intravenous dose of approximately 2 mg, the total plasma clearance of trodopril and trodopril is approximately 52 L/h and 7 L/h, respectively. The renal clearance of trodopril varies from 1 to 4 L/h depending on the dose. Metabolites/Metabolites: Cleavage of the trodopril ester group (primarily in the liver) is the cause of its conversion to the active metabolite, trodopril. Seven other metabolites have been identified, including diketopiperazine and glucuronide conjugates of trodopril and trodopril.
Tredullary is a prodrug with virtually no pharmacological activity until it is hydrolyzed in the liver to tripoprilat.
Tredullary's angiotensin-converting enzyme (ACE) inhibitory activity is primarily attributed to its diacid metabolite, tripoprilat. Cleavage of the tripoprillary ester group (primarily in the liver) is the cause of this conversion.
After oral administration of tripoprillary, approximately 33% of the parent drug and its metabolites are excreted in the urine, primarily as tripoprilat, and approximately 66% are excreted in the feces. In addition to tripoprilat, at least seven other metabolites have been identified, primarily glucuronides or deesterified products.
Biological Half-Life
The elimination half-lives of tripoprillary and tripoprilat are approximately 6 hours and 10 hours, respectively, but similar to all ACE inhibitors, tripoprilat also exhibits a longer terminal elimination phase, in which only a small fraction of the administered drug reaches this stage. This likely represents the binding of the drug to plasma and tissue ACE. Tridopril has an effective elimination half-life of 16-24 hours. At steady state, the effective half-life of tridopril is 22.5 hours.

Toxicity Summary
Identification and Uses: Tridopril is a colorless crystalline solid. Tridopril tablets are indicated for the treatment of hypertension. Human Studies: In humans, the most likely clinical presentation is symptoms of severe hypotension. Expected symptoms of angiotensin-converting enzyme (ACE) inhibitors include hypotension, hyperkalemia, and renal failure. Rare ACE inhibitor-related clinical syndromes initially present as cholestatic jaundice; this condition may progress to fulminant hepatic necrosis and can be fatal. Patients taking ACE inhibitors (including tridopril) should discontinue the medication and be monitored appropriately if jaundice or significantly elevated liver enzymes occur. Use of drugs acting on the renin-angiotensin system in the second and third trimesters of pregnancy can reduce fetal renal function and increase fetal and neonatal morbidity and mortality. The resulting oligohydramnios may be associated with fetal lung hypoplasia and skeletal malformations. Potential neonatal adverse reactions include craniosynostosis, anuria, hypotension, renal failure, and death. Animal studies: In dogs, oral administration of 1000 mg/kg did not result in death or abnormal clinical symptoms. In rats, oral administration of 5000 mg/kg resulted in low mortality (1 in 5 males died; 0 females died). This study investigated the perinatal and postpartum period in female Sprague-Dawley rats, administering trodopril orally at doses of 3, 30, and 300 mg/kg/day from day 17 of gestation to day 21 postpartum. Results showed that offspring in the 30 and 300 mg/kg dose groups had increased incidence of renal pelvis dilation and significantly increased kidney weight, and both groups had higher water intake than the control group. Weight gain in offspring was inhibited in all dose groups, and the survival rate of offspring in the 30 and 300 mg/kg dose groups was slightly lower from day 0 to 4 postpartum compared to the control group. No adverse effects were observed on other postpartum developmental aspects of offspring (e.g., differentiation, sexual maturation, reflexes, motor function, mood, learning ability, and reproductive capacity). No adverse reactions were detected in second-generation offspring.

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Hepatotoxicity
As with other ACE inhibitors, trodopril was associated with a low incidence of elevated serum transaminases (
Probability score: E (unproven but suspected rare cause of clinically significant liver injury)).

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Effects during pregnancy and lactation
◉ Overview of use during lactation
Since there is no information on the use of trodopril during lactation, other medications may be preferred, especially in breastfed newborns or preterm infants.
◉ Effects on breastfed infants
As of the revision date, no relevant published information was found.
◉ Effects on lactation and breast milk
As of the revision date, no relevant published information was found.

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Protein binding
The reduction in serum protein binding of trodopril was approximately 80% (concentration-independent and non-saturable), while the reduction for trodoprilat was 65% to 94% (concentration-related and saturable).

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Interactions
The hypotensive effect of certain inhaled anesthetics may be enhanced by angiotensin-converting enzyme (ACE) inhibitors, including tripdopril.
The risk of angioedema may be increased in patients taking mammalian target of rapamycin (mTOR) inhibitors (e.g., tesimolimus, sirolimus, everolimus).
Nitrosamine reactions (symptoms including facial flushing, nausea, vomiting, and hypotension) have been reported rarely in patients receiving injectable gold preparations (sodium gold thiomalate) and concurrently with angiotensin-converting enzyme (ACE) inhibitors, including tripdopril.
In patients receiving injectable gold preparations, concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 (COX-2) inhibitors, and angiotensin-converting enzyme (ACE) inhibitors (including tripdopril) may lead to worsening of renal function and even acute renal failure, especially in elderly patients, patients with hypovolemia (including those receiving diuretics), or patients with impaired renal function. These effects are usually reversible. Patients receiving trodopril and NSAIDs should have their renal function monitored regularly. NSAIDs may attenuate the antihypertensive effect of ACE inhibitors, including trodopril.
For more complete data on trodopril interactions (9 in total), please visit the HSDB records page.

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Non-human toxicity values
Oral LD50 in male mice: 4875 mg/kg
Oral LD50 in female mice: 3990 mg/kg

[1]. Trandolapril. An update of its pharmacology and therapeutic use in cardiovascular disorders. Drugs. 1998 Nov;56(5):871-93.

[2]. Combination therapy with paricalcitol and trandolapril reduces renal fibrosis in obstructive nephropathy. Kidney Int. 2009 Dec;76(12):1248-57.

[3]. Prevention of arterial structural alterations with verapamil and trandolapril and consequences for mechanical properties in spontaneously hypertensive rats. Eur J Pharmacol. 1998 Nov 13;361(1):51-60.

[4]. Trandolapril inhibits atherosclerosis in the Watanabe heritable hyperlipidemic rabbit. Hypertension. 1992 Oct;20(4):473-7.

Therapeutic Uses
ClinicalTrials.gov is a registry and results database that lists human clinical studies funded by public and private institutions worldwide. The website is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each record on ClinicalTrials.gov includes a summary of the study protocol, including: the disease or condition; the intervention (e.g., the medical product, behavior, or procedure under investigation); the title, description, and design of the study; participation requirements (eligibility criteria); the location of the study; contact information for the study location; and links to relevant information from other health websites, such as the NLM's MedlinePlus (which provides patient health information) and PubMed (which provides citations and abstracts of academic articles in the medical field). The database includes trodopril. Trodopril tablets are indicated for the treatment of hypertension. It can be used alone or in combination with other antihypertensive drugs, such as hydrochlorothiazide. /US Product Label Includes/
Tredupril tablets are indicated for patients with stable conditions who have evidence of left ventricular systolic dysfunction (identifiable by abnormal wall motion) or who develop symptoms of congestive heart failure in the first few days following an acute myocardial infarction. In Caucasian patients, tredupril has been shown to reduce the risk of death (primarily cardiovascular death) and the risk of heart failure-related hospitalization. /US Product Label Includes/
Angiotensin-converting enzyme (ACE) inhibitors are used to treat heart failure, often in combination with other medications such as cardiac glycosides, diuretics, and beta-blockers. /Angiotensin-converting enzyme (ACE) inhibitors; not included on US product label/
For more complete data on the therapeutic uses of tredupril (6 types), please visit the HSDB record page.

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Drug Warning
/Black Box Warning/Tredupril should be discontinued as soon as pregnancy is discovered. Drugs that act directly on the renin-angiotensin system may cause harm or even death to the developing fetus.
It has been reported that patients receiving angiotensin-converting enzyme (ACE) inhibitors, including trodopril, have developed angioedema of the face, extremities, lips, tongue, glottis, and larynx. 0.13% of patients treated with trodopril experienced symptoms resembling angioedema or facial edema. Two of the four cases were life-threatening and resolved with medication (corticosteroids) alone or without treatment. Angioedema associated with laryngeal edema can be fatal. If stridor or angioedema of the face, tongue, or glottis occurs, trodopril should be discontinued immediately, and the patient should be treated according to recognized medical guidelines, closely monitored until the swelling subsides. If the swelling is limited to the face and lips, it usually resolves spontaneously without treatment; antihistamines may help relieve symptoms.
Use of drugs acting on the renin-angiotensin system in the second and third trimesters can reduce fetal kidney function and increase fetal and neonatal morbidity and mortality. The resulting oligohydramnios may be associated with fetal lung hypoplasia and skeletal malformations. Potential neonatal adverse reactions include craniosynostosis, anuria, hypotension, renal failure, and death. Tridopril should be discontinued as soon as pregnancy is confirmed. These adverse outcomes are often associated with use of this type of medication in the second or third trimester. Most epidemiological studies investigating fetal malformations following early pregnancy use of antihypertensive drugs 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. /Angiotensin-converting enzyme (ACE) inhibitors/
Like other angiotensin-converting enzyme (ACE) inhibitors, trodopril rarely causes hypotension in patients with isolated hypertension. However, symptomatic hypotension may occur; high-risk patients include those with severe volume and/or salt loss due to prolonged use of diuretics, dietary salt restriction, dialysis, diarrhea, or vomiting. Volume and/or salt loss should be corrected before initiating trodopril treatment. Significant hypotension may be associated with oliguria and/or progressive azotemia, and in rare cases, can lead to acute renal failure and/or death, which may occur in patients with heart failure (with or without renal impairment). For patients with heart failure, trandopril should be started under close medical supervision at the recommended dose, with close monitoring during the first 2 weeks of treatment and each increase in the dose of trandopril or a diuretic. Hypotension should also be avoided in patients with ischemic heart disease, aortic stenosis, or cerebrovascular disease.
For more complete data on drug warnings for trandopril (13 in total), please visit the HSDB record page.

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Pharmacodynamics
Trandopril is an ethyl ester prodrug of the thiol-free ACE inhibitor trandoprilat.Trandopril is deesterified in the liver to the diacid metabolite trandoprilat, which has approximately eight times the activity of the parent compound as an ACE inhibitor. ACE is a peptidyl dipeptidase and a component of the renin-angiotensin-aldosterone system (RAAS). The RAAS is a mechanism for maintaining homeostasis, regulating hemodynamics, water, and electrolyte balance. Renin is released from the granular cells of the renal juxtaglomeruli when the sympathetic nervous system is excited or when renal blood pressure or blood flow decreases. In the blood, renin cleaves circulating angiotensinogen into angiotensin II (AT1), which is then cleaved by ACE into angiotensin II (AT2). AT2 raises blood pressure through several mechanisms. First, it stimulates the adrenal cortex to secrete aldosterone. Aldosterone reaches the distal convoluted tubule (DCT) and collecting duct of the nephron, promoting sodium and water reabsorption by increasing the number of sodium channels and sodium-potassium ATPases on the cell membrane. Second, angiotensin II (ATII) stimulates the posterior pituitary gland to secrete vasopressin (also known as antidiuretic hormone or ADH). ADH further promotes renal water reabsorption by inserting aquaporin 2 (AQP2) channels into the apical membranes of the distal convoluted tubule and collecting duct cells. Third, ATII raises blood pressure by directly constricting arteries. Stimulation of type I ATII receptors on vascular smooth muscle cells triggers a series of events ultimately leading to muscle cell contraction and vasoconstriction. In addition to these primary effects, ATII also induces a thirst response by stimulating hypothalamic neurons. Angiotensin-converting enzyme inhibitors (ACE inhibitors) inhibit the rapid conversion of angiotensin-converting enzyme I (AT1) to angiotensin-converting enzyme II (AT2) and antagonize the blood pressure increase induced by the renin-angiotensin-aldosterone system (RAAS). ACE (also known as kininase II) is also involved in the enzymatic inactivation of bradykinin (a vasodilator). Inhibition of bradykinin inactivation increases bradykinin levels and further enhances the effects of tripopril by increasing vasodilation and lowering blood pressure. The hypotensive effect of tripopril is due to a decrease in peripheral vascular resistance and is not accompanied by significant changes in urinary chloride, urinary potassium, urinary water, or urinary sodium excretion.

C24H34N2O5

430.54

430.246

87679-37-6

Trandolapril hydrochloride;87725-72-2;Trandolapril-d5;1356847-98-7

5484727

White to off-white solid powder

1.2±0.1 g/cm3

626.0±55.0 °C at 760 mmHg

122-123°C

332.4±31.5 °C

0.0±1.9 mmHg at 25°C

1.549

3.97

2

6

10

31

634

5

CCOC(=O)[C@H](CCC1=CC=CC=C1)N[C@@H](C)C(=O)N2[C@H]3CCCC[C@@H]3C[C@H]2C(=O)O

VXFJYXUZANRPDJ-WTNASJBWSA-N

InChI=1S/C24H34N2O5/c1-3-31-24(30)19(14-13-17-9-5-4-6-10-17)25-16(2)22(27)26-20-12-8-7-11-18(20)15-21(26)23(28)29/h4-6,9-10,16,18-21,25H,3,7-8,11-15H2,1-2H3,(H,28,29)/t16-,18+,19-,20-,21-/m0/s1

(2S,3aR,7aS)-1-[(2S)-2-[[(2S)-1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino]propanoyl]-2,3,3a,4,5,6,7,7a-octahydroindole-2-carboxylic acid

RU 44570 Mavik RU-44570GoptenRU44570 Odrik

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)

DMSO : ~100 mg/mL (~232.27 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (4.83 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 20.8 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: ≥ 2.08 mg/mL (4.83 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (4.83 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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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