Absorption, Distribution and Excretion
Absorbed rapidly after oral administration, with peak plasma concentrations occurring approximately 1 hour later. Bioavailability is 65-75%. After absorption, perindopril is hydrolyzed to perindoprilat, with an average bioavailability of 20%. Food does not affect the rate or extent of absorption. However, food reduces the biotransformation of perindoprilat and decreases its bioavailability by 35%. Extensive metabolism after oral administration; only 4% to 12% of the dose is excreted unchanged in the urine. 219-362 mL/min [oral] hr Metabolism/Metabolites Extensive metabolism; only 4-12% of the dose is excreted unchanged in the urine after oral administration. Six metabolites have been identified: perindoprilat, perindopril glucuronide, perindoprilat glucuronide, one perindopril lactam, and two perindoprilat lactams. Only perindoprilat possesses pharmacological activity. Perindopril and perindopril glucuronide are two major circulating metabolites. The known metabolite of perindopril is perindopril glucuronide. The biological half-life of perindopril is 1.2 hours; that of perindopril is 30–120 hours. The longer half-life of perindopril is due to its slow dissociation from its ACE binding site.

Hepatotoxicity
Perindopril, like other ACE inhibitors, 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)). Pregnancy and Lactation Effects ◉ Overview of Lactation Use: Limited information suggests that only low concentrations of perindopril and its active metabolites have been detected in breast milk, consistent with other drugs in the same class. The amount ingested by infants is minimal and no adverse effects are expected on breastfed infants. ◉ Effects on Breastfed Infants: Ten infants were breastfed by mothers taking 5 to 20 mg/day of perindopril (feeding extent not specified). All infants reported normal growth and development according to parents. ◉ Effects on Lactation: Breast Milk: As of the revision date, no relevant published information was found. Protein Binding Perindopril binds to plasma proteins in a rate of 10-20%.

[1]. Angiotensin receptor blockade modulates NFκB and STAT3 signaling and inhibits glial activation and neuroinflammation better than angiotensin-converting enzyme inhibition . Molecular neurobiology, 2016, 53: 6950-6967.

[2]. Combination of perindopril erbumine and huangqi-danshen decoction protects against chronic kidney disease via sirtuin3/mitochondrial dynamics pathway . Evidence-Based Complementary and Alternative Medicine, 2022, 2022.

[3]. Pharmacodynamic evaluation of 4 angiotensin‐converting enzyme inhibitors in healthy adult horses . Journal of veterinary internal medicine, 2013, 27(5): 1185-1192.

[4]. Dose-dependent effects of perindopril on blood pressure and small-artery structure . Hypertension, 1994, 23(5): 659-666.

Perindopril is an α-amino acid ester, an ethyl ester of N-{(2S)-1-[(2S,3aS,7aS)-2-carboxyoctahydro-1H-indol-1-yl]-1-oxopropyl-2-yl}-L-n-valine. It is an EC 3.4.15.1 (peptidyl dipeptidase A) inhibitor and an antihypertensive drug. It is an α-amino acid ester, a dicarboxylic acid monoester, an organic heterobicyclic compound, and an ethyl ester. It is the conjugate acid of perindopril (1-). Perindopril is a non-thiol prodrug belonging to the angiotensin-converting enzyme (ACE) inhibitor class of drugs. After oral administration, it is rapidly metabolized in the liver to the active metabolite perindopril. Perindopril is a potent competitive ACE inhibitor; ACE is the enzyme responsible for converting angiotensin I (ATI) to angiotensin II (ATI). Angiotensin-converting enzyme (ACE) regulates blood pressure and is a key component of the renin-angiotensin-aldosterone system (RAAS). Perindopril can be used to treat mild to moderate essential hypertension, mild to moderate congestive heart failure, and to reduce cardiovascular risk in patients with hypertension, post-myocardial infarction, and stable coronary artery disease. Perindopril is an angiotensin-converting enzyme inhibitor. Its mechanism of action is as an angiotensin-converting enzyme inhibitor. Perindopril is an angiotensin-converting enzyme (ACE) inhibitor used to treat hypertension and stable coronary artery disease. Transient elevation of serum transaminases caused by perindopril is rare but has been associated with rare cases of acute liver injury. Perindopril is a non-sulfhydryl angiotensin-converting enzyme (ACE) inhibitor with antihypertensive effects. Upon hydrolysis, perindopril is converted to its active form, perindoprilat, which inhibits the conversion of ACE and angiotensin I to angiotensin II. Therefore, angiotensin II-mediated vasoconstriction and angiotensin II-stimulated aldosterone secretion from the adrenal cortex are suppressed, leading to diuresis and increased sodium excretion. An angiotensin-converting enzyme inhibitor. It is used to treat patients with hypertension and heart failure. See also: Perindopril tert-butylamine (salt form). Drug Indications For the treatment of mild to moderate essential hypertension, mild to moderate congestive heart failure, and to reduce cardiovascular risk in patients with hypertension, myocardial infarction, and stable coronary artery disease. FDA Label Mechanism of Action ACE has two isoenzymes: the somatic isoenzyme, a glycoprotein composed of a single-chain polypeptide of 1277 amino acids; and the testicular isoenzyme, with a lower molecular weight, believed to play a role in sperm maturation and sperm binding to fallopian tube epithelial cells. Somatic ACE has two functionally active domains, the N domain and the C domain, which are generated by tandem gene repetitions. Although these two domains have high sequence similarity, they play different physiological roles. The C domain is mainly involved in blood pressure regulation, while the N domain plays a role in hematopoietic stem cell differentiation and proliferation. ACE inhibitors can bind to both domains and inhibit their activity, but the affinity and inhibitory activity for the C domain are much higher than for the N domain. Perindopril's active metabolite, perindoprilat, competitively binds to ACE with angiotensin II (ATI) and inhibits the enzymatic hydrolysis of ATI to ATII. As described in the "Pharmacology" section above, reducing ATII levels in vivo can lower blood pressure by inhibiting the pressor effect of ATII. Perindopril also leads to increased plasma renin activity, possibly due to loss of feedback inhibition of renin release mediated by angiotensin II (ATII) and/or through baroreceptor stimulation reflex mechanisms.

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Pharmacodynamics
Oral perindopril is a non-sulfhydryl prodrug that is metabolized via first-pass metabolism (62%) and systemic hydrolysis (38%) to its active metabolite, perindoprilat. Perindoprilat lowers blood pressure by antagonizing the renin-angiotensin-aldosterone system (RAAS). The RAAS is a homeostatic mechanism that regulates hemodynamics, water, and electrolyte balance. Renin is released from the granulocytes 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-converting enzyme I (ATI), which is then cleaved by angiotensin-converting enzyme (ACE) into angiotensin-converting enzyme II (ATII). Angiotensin II (ATII) 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. Secondly, ATII stimulates the posterior pituitary gland to secrete angiotensin (also known as antidiuretic hormone or ADH). ADH further promotes renal water reabsorption by inserting aquaporin 2 (AQP2) channels into the apical membrane of distal convoluted tubule and collecting duct cells. Thirdly, 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, angiotensin II (ATII) also induces a thirst response by stimulating hypothalamic neurons. Angiotensin-converting enzyme inhibitors (ACEIs) inhibit the rapid conversion of angiotensin-converting enzyme I (ATI) to angiotensin-converting enzyme II (ATII) and antagonize the blood pressure increase induced by the renin-angiotensin-aldosterone system (RAAS). Angiotensin-converting enzyme (also known as kallikrein II) is also involved in the enzymatic inactivation of bradykinin, a vasodilator. Inhibiting bradykinin inactivation increases bradykinin levels and maintains the effects of perindopril by enhancing vasodilation and lowering blood pressure.

C₁₉H₃₂N₂O₅

368.47

368.231

82834-16-0

Perindopril erbumine;107133-36-8

107807

Off-white to light yellow solid powder

1.1±0.1 g/cm3

537.4±45.0 °C at 760 mmHg

100-101°C

278.8±28.7 °C

0.0±3.1 mmHg at 25°C

1.512

3.36

2

6

9

26

524

5

CCC[C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@H]2CCCC[C@H]2C[C@H]1C(=O)O

IPVQLZZIHOAWMC-QXKUPLGCSA-N

InChI=1S/C19H32N2O5/c1-4-8-14(19(25)26-5-2)20-12(3)17(22)21-15-10-7-6-9-13(15)11-16(21)18(23)24/h12-16,20H,4-11H2,1-3H3,(H,23,24)/t12-,13-,14-,15-,16-/m0/s1

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

S 9490; S-9490

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)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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