Benazepril targets the angiotensin-converting enzyme (ACE), which is a key component of the renin-angiotensin-aldosterone system (RAAS). By inhibiting ACE, benazepril prevents the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor. This leads to vasodilation, reduced blood pressure, decreased aldosterone secretion, and reduced sodium and water retention.

In vitro, benazeprilat, the active metabolite, inhibits ACE activity. This is measured by its ability to prevent the conversion of the synthetic substrate hippuryl-histidyl-leucine (HHL) to hippuric acid by ACE. The IC50 of benazeprilat for ACE inhibition is typically in the low nanomolar range, indicating high potency.

In vivo, benazepril lowers blood pressure in hypertensive patients by reducing peripheral vascular resistance. It is effective in treating essential hypertension and can be used alone or in combination with other antihypertensive agents. It also reduces the workload on the heart and is used in the management of heart failure. Its effects are dose-dependent and sustained over 24 hours.

The in vitro enzyme inhibition assay for benazepril involves measuring the activity of ACE in the presence of the active metabolite, benazeprilat. ACE is incubated with the substrate hippuryl-histidyl-leucine (HHL) in a suitable buffer. The reaction is stopped, and the amount of hippuric acid produced is measured by spectrophotometry or HPLC. The IC50 of benazeprilat is determined by plotting the percent inhibition against concentration.

In vitro cellular assays for benazepril are not typically performed, as its mechanism of action does not involve cellular receptor activation. Its effects are measured at the enzymatic level. However, the downstream effects of ACE inhibition, such as reduced angiotensin II production, can be measured in cell culture systems (e.g., endothelial cells) that respond to angiotensin II stimulation.

In vivo animal experiments for benazepril are typically conducted in hypertensive rat models, such as the spontaneously hypertensive rat (SHR). Blood pressure is measured via tail-cuff or telemetry before and after oral administration of benazepril. The reduction in systolic and diastolic blood pressure is recorded over time to establish the dose-response relationship and duration of action.

Absorption, Distribution and Excretion
The bioavailability of oral benazepril in horses is 3% to 4%. In humans, at least 37% of orally administered benazepril is absorbed, reaching peak plasma concentrations within 0.5 to 1 hour. Other studies have shown a median peak plasma concentration of 1.5 hours. In healthy subjects with normal renal function, benazepril and benazeprilat are primarily eliminated via renal excretion. In healthy subjects, non-renal (i.e., bile) excretion accounts for approximately 11%–12% of benazeprilat excretion. A final population pharmacokinetic model from one study estimated the volume of distribution to be 203 ± 69.9 L. A final population pharmacokinetic model from another study estimated the clearance to be 129 ± 30.0 L. /Breast Milk/ Only trace amounts of unchanged benazepril and benazeprilat are excreted in the breast milk of lactating women taking benazepril. If a newborn is exclusively breastfed, the ingested dose of benazepril and benazeprilat (mg/kg) is less than 0.1% of the maternal dose. Benazepril and benazeprilat are primarily eliminated through renal excretion. After oral administration, approximately 37% of the drug is excreted in the urine as benazeprilat (20%), benazeprilat glucuronide (8%), benazeprilat glucuronide (4%), and trace amounts of benazepril. Non-renal (i.e., bile) excretion accounts for approximately 11%–12% of benazeprilat excretion. The effective half-life of benazeprilat is 10–11 hours after repeated once-daily oral administration of benazepril hydrochloride. Therefore, steady-state plasma concentrations of benazeprilat should be achieved after 2–3 once-daily oral administrations of benazeprilat hydrochloride. The cumulative ratio (based on AUC) of benazeprilat after once-daily administration is 1.19.

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Metabolism/Metabolites
Ester cleavage (primarily in the liver) converts benazepril into its active metabolite, benazeprilat. Both benazepril and benazeprilat are conjugated with glucuronic acid before excretion in the urine.
Benazepril and benazeprilat are primarily eliminated via renal excretion. Approximately 37% of the orally administered dose is recovered in the urine as benazeprilat (20%), benazeprilat glucuronide (8%), benazeprilat glucuronide (4%), and trace amounts of benazepril. Non-renal (i.e., bile) excretion accounts for approximately 11%–12% of benazeprilat excretion. The effective half-life of benazeprilat is 10 to 11 hours after repeated oral administration of benazepril hydrochloride once daily. Therefore, steady-state concentrations of benazeprilat should be reached after 2 to 3 oral doses of benazepril hydrochloride once daily. Following once-daily administration, the cumulative ratio based on benazepril's AUC was 1.19. In healthy dogs, after oral administration, benazepril is rapidly absorbed and converted to the active metabolite benazepril, with peak plasma concentrations occurring approximately 75 minutes after administration. Benazepril is almost entirely metabolized to benazepril via ester cleavage (primarily in the liver). Both benazepril and benazepril undergo glucuronidation. Biological Half-Life: The half-life of the prodrug benazepril is 2.7 ± 8.5 hours. The half-life of the active metabolite benazepril is 22.3 ± 9.2 hours. The accumulation half-life of benazepril is 10 to 11 hours. In healthy dogs, the elimination half-life of benazepril is approximately 3.5 hours.
After repeated oral administration of benazepril hydrochloride once daily, the effective half-life of benazepril is 10 to 11 hours.
Benazepril is a prodrug that is rapidly and extensively metabolized in the liver to its active metabolite, benazeprilat. The bioavailability of benazeprilat is approximately 30%. The drug reaches peak plasma concentrations in about 1-2 hours, and benazeprilat reaches peak levels in about 2-4 hours. The effective half-life of benazeprilat is approximately 10-11 hours, allowing for once-daily dosing. It is primarily eliminated by the kidneys.

Toxicity Summary
Identification and Use: Benazepril is a non-sulfonyl angiotensin-converting enzyme (ACE) inhibitor. It is used to treat hypertension and heart failure in humans and animals. Human Studies: Anaphylactic reactions, including anaphylactoid reactions and angioedema (including laryngeal angioedema and tongue edema), can be fatal. Head and neck angioedema involving the tongue, glottis, or larynx can lead to airway obstruction. Rare ACE inhibitor-related clinical syndromes initially present as cholestatic jaundice, which may progress to fulminant hepatic necrosis and can be fatal. Patients taking ACE inhibitors (including benazepril) should discontinue the drug and be monitored appropriately if jaundice or significantly elevated liver enzymes develop. No reports of benazepril overdose in humans have been found, but the most common manifestation of benazepril overdose is likely hypotension, usually treated with intravenous saline infusion. Hypotension may be accompanied by electrolyte disturbances and renal failure. Use of drugs acting on the renin-angiotensin system in the mid-to-late stages of pregnancy can reduce fetal renal function and increase fetal and neonatal morbidity and mortality. The resulting oligohydramnios may be associated with fetal pulmonary hypoplasia and skeletal malformations. Potential neonatal adverse reactions include craniosynostosis, anuria, hypotension, renal failure, and death. Animal studies: A single oral dose of 3 g/kg benazepril in mice resulted in significant mortality. However, rats tolerated single oral doses up to 6 g/kg. Reduced activity was observed in mice at 1 g/kg and in rats at 5 g/kg. Benazepril had no adverse effects on reproductive function in male and female rats at doses ranging from 50 to 500 mg/kg/day. No evidence of carcinogenicity was found in rats and mice administered benazepril at doses up to 150 mg/kg/day for up to two years. No mutagenic activity was detected in the Ames test for bacteria (with or without metabolic activation), in vitro positive mutation assays in cultured mammalian cells, or nuclear abnormality assays.

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Hepatotoxicity
As with other ACE inhibitors, benazepril is associated with a low incidence of elevated serum transaminases (
Probability score: D (likely a rare cause of clinically significant liver injury)).

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Effects during pregnancy and lactation
◉ Overview of use during lactation
Because benazepril is present in low amounts in breast milk, the amount ingested by infants is minimal, and no adverse effects are expected on breastfed infants.
◉ Effects on breastfed infants
As of the revision date, no relevant published information was found.
◉ Effects on breastfeeding Breast milk
As of the revision date, no relevant published information was found.

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Protein binding
The protein binding rate of benazepril is 96.7%, and that of benazepril is 95.3%.

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Interactions
Because ACE inhibitors may promote kinin-mediated prostaglandin synthesis and/or release, concomitant use of drugs that inhibit prostaglandin synthesis (such as aspirin and ibuprofen) may reduce the antihypertensive effect of ACE inhibitors (including enalapril). Limited data suggest that concomitant use of ACE inhibitors with nonsteroidal anti-inflammatory drugs (NSAIDs) may sometimes lead to an acute decline in renal function; however, the possibility that such an effect may occur when one drug is used alone cannot be ruled out. …Aspirin and other NSAIDs may also attenuate the hemodynamic effects of ACE inhibitors in patients with congestive heart failure. This is because ACE inhibitors enhance the compensatory hemodynamic mechanisms of heart failure. Aspirin and other NSAIDs do not interact directly with ACE inhibitors, but rather with these compensatory mechanisms. These beneficial mechanisms are particularly susceptible to this interaction, leading to a potential loss of clinical benefit. Therefore, the more severe the heart failure and the more pronounced the compensatory mechanisms, the more significant the interaction between NSAIDs and ACE inhibitors. Even when using optimal doses of ACE inhibitors in the treatment of congestive heart failure, potential cardiovascular and survival benefits may not be observable if patients are concurrently taking NSAIAs. In multiple multicenter studies, concomitant NSAIAs (e.g., a single 350 mg aspirin dose) in patients with congestive heart failure have suppressed the beneficial hemodynamic effects associated with ACE inhibitors, thus diminishing the beneficial effects of these drugs on survival and cardiovascular disease incidence. /ACE Inhibitors/
Concomitant treatment with angiotensin-converting enzyme inhibitors and mTOR inhibitors (e.g., tesimolimus, sirolimus, everolimus) may increase the risk of angioedema. Signs of angioedema should be monitored. /ACE Inhibitors/
Dual blockade of the renin-angiotensin system (RAS) with angiotensin receptor blockers, ACE inhibitors, or alisartan compared to monotherapy increases the risk of hypotension, hyperkalemia, and changes in renal function (including acute renal failure). Most patients receiving combination therapy with two RAS inhibitors did not experience any additional benefit compared to monotherapy. Concomitant use of RAS inhibitors should generally be avoided. Patients taking listifenoxate and other medications that affect RAS should have their blood pressure, renal function, and electrolytes closely monitored. Diabetic patients should not take alistifenoxate and listifenoxate concurrently. Patients with renal insufficiency (glomerular filtration rate <60 mL/min) should avoid concurrent use of alistifenoxate and listifenoxate.
Rare reports of hypoglycemia in diabetic patients: Patients taking angiotensin-converting enzyme (ACE) inhibitors (including benazepril) and who are also taking insulin or oral hypoglycemic agents should be informed of the possibility of hypoglycemia and be appropriately monitored.
For more complete data on drug interactions of benazepril (out of 10), please visit the HSDB records page.
Benazepril is generally well-tolerated. Common side effects include cough (due to bradykinin accumulation), hypotension, dizziness, and headache. More serious but rare side effects include angioedema (swelling of the face, lips, and throat), hyperkalemia, and renal impairment. It is contraindicated in pregnancy (can cause fetal toxicity) and in patients with a history of angioedema related to ACE inhibitor therapy.

Arzneimittelforschung.1991 Jun;41(6):602-7;J Vet Med Sci.2007 Oct;69(10):1015-23.

Benazepril is a benzodiazepine compound, a derivative of benazepril, in which the carboxyl group of the 2-amino-4-phenylbutyric acid moiety is converted to the corresponding ethyl ester. It (usually in hydrochloride form) is used as a prodrug of the angiotensin-converting enzyme inhibitor benazepril for the treatment of hypertension and heart failure. It is an EC 3.4.15.1 (peptidyl dipeptidase A) inhibitor and prodrug. It is a benzodiazepine compound, a dicarboxylic acid monoester, an ethyl ester, and a lactam. It is functionally related to benazepril. It is the conjugate base of benazepril(1+). Benazepril, brand name Losin, is a drug used to treat hypertension, congestive heart failure, and chronic renal failure. Benazepril is converted to its active form, benazepril, a non-thiol angiotensin-converting enzyme (ACE) inhibitor, by hepatic hydrolysis of the ester group. Benazepril is an angiotensin-converting enzyme inhibitor. Benazepril's mechanism of action is as an angiotensin-converting enzyme (ACE) inhibitor. Benazepril's physiological effect is achieved by lowering blood pressure. Benazepril is a widely used ACE inhibitor for the treatment of hypertension. Transient elevations in serum transaminases caused by benazepril are rare but have been associated with rare cases of acute liver injury. Benazepril is a carboxyl-containing ACE inhibitor with antihypertensive activity. As a prodrug, benazepril is metabolized to its active form, benazeprilat. Benazeprilat competitively binds to and inhibits the activity of ACE, thereby blocking the conversion of angiotensin I to angiotensin II. This prevents the potent vasoconstrictive effect of angiotensin II, leading to vasodilation. Benazeprilat also reduces adrenal cortex aldosterone secretion for angiotensin II, thereby increasing sodium excretion and consequently increasing water excretion. See also: Benazepril hydrochloride (salt form); D&C Yellow 10 (active ingredient); Amlodipine besylate; Benazepril hydrochloride (note moved to).

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Drug Indications
Benapril is indicated for the treatment of hypertension. It can be used alone or in combination with thiazide diuretics.
FDA Label
Mechanism of Action
Benapril is the active metabolite of benazepril. It competitively binds to angiotensin-converting enzyme (ACE) with angiotensin I, thereby blocking the conversion of angiotensin I to angiotensin II. ACE inhibition leads to a decrease in plasma angiotensin II levels. Since angiotensin II is a vasoconstrictor and a negative feedback regulator of renin activity, its reduced concentration leads to a decrease in blood pressure and stimulates baroreceptor reflex mechanisms, resulting in decreased vasopressor activity and reduced aldosterone secretion.

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Therapeutic Use
/Clinical Trials/ ClinicalTrials.gov is a registry and results database that includes publicly and privately funded human clinical studies worldwide. This website is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each record on ClinicalTrials.gov provides summary information on the study protocol, including: disease or condition; intervention (e.g., the medical product, behavior, or procedure being studied); study title, description, and design; participation requirements (eligibility criteria); study location; 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). Benazepril is included in this database. Losartan 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. …It can be used alone or in combination with thiazide diuretics. /US product label includes/ 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 listed on the US product label/
Both ACE inhibitors and angiotensin II receptor antagonists have been shown to slow the progression of kidney disease in patients with diabetes and persistent proteinuria. For such patients with mildly elevated urinary albumin excretion (30-300 mg/24 hours) or higher (more than 300 mg/24 hours), one class of drugs is recommended. For patients with severely impaired renal function, the usual precautions for ACE inhibitor or angiotensin II receptor antagonist therapy should be observed. /Angiotensin-converting enzyme (ACE) inhibitors; not listed on the US product label/
For more complete data on the therapeutic uses of benazepril (7 types), please visit the HSDB record page.

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Drug Warning
/Black box warning/If pregnancy is discovered, discontinue lisinopril as soon as possible. Drugs that act directly on the renin-angiotensin system may cause damage or even death to the developing fetus.
A rare angiotensin-converting enzyme (ACE) inhibitor-related clinical syndrome initially presents as cholestatic jaundice; it may progress to fulminant hepatic necrosis and can be fatal. Patients taking ACE inhibitors (including benazepril) should discontinue the medication and be monitored appropriately if jaundice or significantly elevated liver enzymes occur.
Patients taking lisinopril should have their serum potassium levels monitored regularly. Drugs that inhibit the renin-angiotensin system may cause hyperkalemia. Risk factors for hyperkalemia include renal insufficiency, diabetes, and concomitant use of potassium-sparing diuretics, potassium supplements, and/or potassium-containing salt substitutes. Adverse reactions occurring in more than 1% of patients taking benazepril include headache, dizziness, fatigue, somnolence, orthostatic vertigo, nausea, and cough. Adverse reactions occurring in more than 1% of patients taking benazepril and hydrochlorothiazide fixed-dose combination preparations include dizziness, fatigue, orthostatic vertigo, headache, cough, increased muscle tone, vertigo, nausea, impotence, and somnolence. Adverse reactions occurring in more than 1% of patients taking benazepril and amlodipine fixed-dose combination formulations include cough, headache, dizziness, and edema. For more complete data on drug warnings for benazepril (16 total), please visit the HSDB record page. Pharmacodynamics: Benazepril is an angiotensin-converting enzyme (ACE) inhibitor, a prodrug that is hydrolyzed by esterases to the active drug benazeprilat. It is used to treat hypertension and heart failure, reduce proteinuria and kidney disease in patients with renal disease, and prevent stroke, myocardial infarction, and sudden cardiac death in high-risk patients. Benazepril and benazeprilat inhibit angiotensin-converting enzyme (ACE) in humans and animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor angiotensin II. Angiotensin II also stimulates the adrenal cortex to secrete aldosterone.
Benazepril is marketed under the brand name Lotensin. It was approved by the FDA in 1991. It is available as oral tablets, often in combination with hydrochlorothiazide (Lotensin HCT) for enhanced antihypertensive efficacy. It is a cornerstone therapy for hypertension and heart failure, and it has been shown to reduce cardiovascular morbidity and mortality in patients with these conditions.

C24H28N2O5

424.4895

424.199

86541-75-5

Benazepril hydrochloride;86541-74-4

5362124

White to off-white solid powder

1.3±0.1 g/cm3

691.2±55.0 °C at 760 mmHg

133-135 °C(lit.)

371.8±31.5 °C

0.0±2.3 mmHg at 25°C

1.608

3.86

2

6

10

31

619

2

C(N1C(=O)[C@@H](N[C@H](C(=O)OCC)CCC2C=CC=CC=2)CCC2C=CC=CC1=2)C(=O)O

XPCFTKFZXHTYIP-PMACEKPBSA-N

InChI=1S/C24H28N2O5/c1-2-31-24(30)20(14-12-17-8-4-3-5-9-17)25-19-15-13-18-10-6-7-11-21(18)26(23(19)29)16-22(27)28/h3-11,19-20,25H,2,12-16H2,1H3,(H,27,28)/t19-,20-/m0/s1

2-[(3S)-3-[[(2S)-1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino]-2-oxo-4,5-dihydro-3H-1-benzazepin-1-yl]acetic 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)

DMSO: ~100 mg/mL (~235.6 mM; with ultrasonication)

Solubility in Formulation 1: 2.5 mg/mL (5.89 mM) in 10% DMSO + 40% PEG300 + 5% Tween-80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), Clear solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of DMSO stock solution (25.0 mg/mL) to 400 μL of PEG300 and mix well; then add 50 μL of Tween-80 and mix well; finally add 450 μL of physiological saline and 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: 2.5 mg/mL (5.89 mM) 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; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of DMSO stock solution (25.0 mg/mL) to 900 μL of 20% SBE-β-CD saline and mix well.
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: 2.5 mg/mL (5.89 mM) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), Clear solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of DMSO stock solution (25.0 mg/mL) to 900 μL of corn oil and mix well.

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