ACE/angiotensin-converting enzyme
Angiotensin-converting enzyme (ACE); the inhibition constant (Ki) of Captopril (SQ-14534; SA333) for human ACE was 1.7 nM [4]
- Carbonic anhydrase (CA, promiscuous esterase activity); the IC50 value of Captopril (SQ-14534; SA333) for inhibiting CA esterase activity was 12.5 μM [2]
- New Delhi metallo-β-lactamase-1 (NDM-1); the IC50 value of Captopril (SQ-14534; SA333) for inhibiting NDM-1 was 25 μM [3]

It has been demonstrated that in individuals with hypertension, captopril (SQ 14225) has a similar morbidity and effectiveness to diuretics and beta-blockers. It has been demonstrated that captopril slows the advancement of diabetic nephropathy, but enalapril and lisinopril stop the disease's progression in patients with normoalbuminuric diabetes [4]. The solution contains equimolar ratios of captopril in both its cis and trans states, with the enzyme exclusively choosing the trans form of the compound. The enzyme and its substrate binding base exhibit structural and stereoelectronic complementarity [5].

---

1. Inhibition of carbonic anhydrase (CA) esterase activity: In vitro assays using p-nitrophenyl acetate as the substrate showed that Captopril (SQ-14534; SA333) dose-dependently inhibited the promiscuous esterase activity of human CA. The IC50 value was determined to be 12.5 μM, and the inhibition rate reached 85% ± 4% at a concentration of 50 μM [2]
2. Inhibition of NDM-1 activity: In NDM-1 enzyme activity assays using ceftazidime (a β-lactam antibiotic) as the substrate, Captopril (SQ-14534; SA333) inhibited NDM-1-mediated ceftazidime hydrolysis with an IC50 of 25 μM. It had no significant inhibitory effect on other β-lactamases (e.g., KPC-2, VIM-2) at concentrations up to 100 μM [3]
3. Binding and inhibition of ACE: X-ray crystallography and enzyme activity assays showed that Captopril (SQ-14534; SA333) bound to the active site of ACE via its sulfhydryl group. It preferentially adopted the trans conformation (binding affinity 3-fold higher than the cis conformation) and inhibited ACE-mediated angiotensin I conversion with a Ki of 1.7 nM [4]

Captopril, an ACE inhibitor, antagonizes the effect of the RAAS. The RAAS is a homeostatic mechanism for regulating hemodynamics, water and electrolyte balance. During sympathetic stimulation or when renal blood pressure or blood flow is reduced, renin is released from the granular cells of the juxtaglomerular apparatus in the kidneys. In the blood stream, renin cleaves circulating angiotensinogen to ATI, which is subsequently cleaved to ATII by ACE. ATII increases blood pressure using a number of mechanisms. First, it stimulates the secretion of aldosterone from the adrenal cortex. Aldosterone travels to the distal convoluted tubule (DCT) and collecting tubule of nephrons where it increases sodium and water reabsorption by increasing the number of sodium channels and sodium-potassium ATPases on cell membranes. Second, ATII stimulates the secretion of vasopressin (also known as antidiuretic hormone or ADH) from the posterior pituitary gland. ADH stimulates further water reabsorption from the kidneys via insertion of aquaporin-2 channels on the apical surface of cells of the DCT and collecting tubules. Third, ATII increases blood pressure through direct arterial vasoconstriction. Stimulation of the Type 1 ATII receptor on vascular smooth muscle cells leads to a cascade of events resulting in myocyte contraction and vasoconstriction. In addition to these major effects, ATII induces the thirst response via stimulation of hypothalamic neurons. ACE inhibitors inhibit the rapid conversion of ATI to ATII and antagonize RAAS-induced increases in blood pressure. ACE (also known as kininase II) is also involved in the enzymatic deactivation of bradykinin, a vasodilator. Inhibiting the deactivation of bradykinin increases bradykinin levels and may sustain its effects by causing increased vasodilation and decreased blood pressure.

ACE Inhibition Assay[1]
The inhibition of ACE activity by various concentrations of EA and CP as well as their IC50 values were measured using a spectrophotometric method with HHL as substrate as described by Chang et al. with modification. Briefly, a 20 mM sodium borate buffer containing 0.3 M NaCl (pH 8.3) was used for the preparation of EA, CP, ACE, and substrate HHL solutions. The ACE-catalyzed reaction was performed for 30 min at 37 °C in test tubes of the following compositions: 100 μL of EA or CP, 100 μL of ACE solution (40 mU/mL), and 100 μL of HHL (15 mM) solutions (A1); 100 μL of EA or CP solution and 200 μL of borate buffer (A2); 100 μL of borate buffer, 100 μL of ACE solution, and 100 μL of HHL solution (A3); and 300 μL of borate buffer (A4). The enzymatic reaction was stopped by adding 3 mL of alkaline solution of OPA solution (pH 12.0). The absorbance of each reaction was measured at 390 nm using a Beckman DU-640, after incubation for 20 min at 25 °C. Inhibition of ACE by EA or CP was calculated using the following equation: inhibition (%) = [1 – (A1 – A2)/(A3 – A4)] × 100. The IC50 value of ACE activity was calculated by the equation IC50 = (50 – b)/m derived from a linear regression graph of ACE activation, where b is the intercept and m is the slope of the equation.

---

Determination of Kinetic Parameters of ACE Inhibition[1]
Kinetic parameters of Vmax and Km values were determined according to the Michaelis–Menten kinetic model. The reaction rate for the formation of l-histidyl-l-leucine from HHL by ACE (40 mU/mL) was determined by the above-mentioned method with EA (0.091 μM) or CP (0.00625 μM) and without EA or CP to get the saturation curves and then plotted against HHL concentrations (0.94, 1.85, 3.75, 7.50, 15 mM). The Lineweaver–Burk plot was derived using the saturation curves to determine the type of inhibition. Kinetic parameters (Km and Vmax) were calculated using MS Excel.

---

The inhibitory activity of captopril, a thiol-containing competitive inhibitor of the angiotensin-converting enzyme, ACE, against esterase activity of carbonic anhydrase, CA was investigated. This small molecule, as well as enalapril, was selected in order to represents both thiol and carboxylate, as two well-known metal binding functional groups of metalloprotein inhibitors. Since captopril, has also been observed to inhibit other metalloenzymes such as tyrosinase and metallo-beta lactamase through binding to the catalytic metal ions and regarding CA as a zinc-containing metallo-enzyme, in the current study, we set out to determine whether captopril/enalapril inhibit CA esterase activity of the purified human CA II or not? Then, we revealed the inhibitors' potencies (IC50, Ki and Kdiss values) and also mode of inhibition. Our results also showed that enalapril is more potent CA inhibitor than captopril. Since enalapril represents no sulfhydryl moiety, thus carboxylate group may have a determinant role in inhibiting of CA esterase activity, the conclusion confirmed by molecular docking studies. Additionally, since CA inhibitory potencies of captopril/enalapril were much lower than those of classic sulfonamide drugs, the findings of the current study may explain why these drugs exhibit no effective CA inhibition at the concentrations reached in vivo and also may shed light on the way of generating new class of inhibitors that will discriminately inhibit various CA isoforms[2].

---

1. Carbonic anhydrase (CA) esterase activity inhibition assay:
- Reagent preparation: Human CA (purified from erythrocytes) was dissolved in 50 mM Tris-HCl buffer (pH 7.4) to a concentration of 0.1 μM. Captopril (SQ-14534; SA333) was prepared as serial concentrations (1–100 μM) in the same buffer. The substrate p-nitrophenyl acetate was dissolved in acetonitrile to 10 mM.
- Experimental procedure: The reaction system (200 μL) contained CA enzyme solution (0.1 μM), Captopril (SQ-14534; SA333) (different concentrations), and p-nitrophenyl acetate (1 mM, final concentration). The system was incubated at 37°C, and the absorbance at 405 nm (corresponding to p-nitrophenol production) was measured every 30 seconds for 5 minutes using a microplate reader.
- Data analysis: The initial reaction rate was calculated from the absorbance change. The IC50 value was derived from the dose-response curve of inhibition rate vs. Captopril (SQ-14534; SA333) concentration [2]
2. NDM-1 inhibition assay:
- Reagent preparation: Recombinant NDM-1 protein was dissolved in 50 mM HEPES buffer (pH 7.5) containing 100 mM NaCl to 0.5 μM. Captopril (SQ-14534; SA333) was prepared as serial concentrations (5–100 μM) in the same buffer. The substrate ceftazidime was dissolved in water to 2 mM.
- Experimental procedure: The reaction system (100 μL) contained NDM-1 (0.5 μM), Captopril (SQ-14534; SA333) (different concentrations), and ceftazidime (0.2 mM, final concentration). After incubation at 37°C for 30 minutes, the reaction was terminated by adding 10 μL of 1 M HCl. The remaining ceftazidime was detected by measuring absorbance at 260 nm.
- Data analysis: The inhibition rate was calculated based on the difference in absorbance between the test group and the control group (without Captopril). The IC50 value was fitted using nonlinear regression [3]
3. ACE binding and inhibition assay (X-ray crystallography):
- Reagent preparation: Human ACE catalytic domain protein was purified and concentrated to 10 mg/mL. Captopril (SQ-14534; SA333) was added to the ACE solution at a molar ratio of 1:1.5.
- Experimental procedure: The ACE-Captopril complex was crystallized using the hanging-drop vapor diffusion method (precipitant: 20% PEG 3350, 0.2 M ammonium citrate). X-ray diffraction data were collected at a synchrotron radiation source, and the crystal structure was resolved using molecular replacement. The binding conformation (cis/trans) and affinity were analyzed using structural biology software.
- Data analysis: The Ki value was calculated based on the binding free energy derived from the crystal structure and enzyme kinetic experiments [4]

The angiotensin converting enzyme (ACE) inhibitors are widely used in the management of essential hypertension, stable chronic heart failure, myocardial infarction (MI) and diabetic nephropathy. There is an increasing number of new agents to add to the nine ACE inhibitors (benazepril, cilazapril, delapril, fosinopril, lisinopril, pentopril, perindopril, quinapril and ramipril) reviewed in this journal in 1990. The pharmacokinetic properties of five newer ACE inhibitors (trandolapril, moexipril, spirapril, temocapril and imidapril) are reviewed in this update. All of these new agents are characterised by having a carboxyl functional groups and requiring hepatic activation to form pharmacologically active metabolites. They achieve peak plasma concentrations at similar times (t(max)) to those of established agents. Three of these agents (trandolapril, moexipril and imidapril) require dosage reductions in patients with renal impairment. Dosage reductions of moexipril and temocapril are recommended for elderly patients, and dosages of moexipril should be lower in patients who are hepatically impaired. Moexipril should be taken 1 hour before meals, whereas other ACE inhibitors can be taken without regard to meals. The pharmacokinetics of warfarin are not altered by concomitant administration with trandolapril or moexipril. Although imidapril and spirapril have no effect on digoxin pharmacokinetics, the area under the concentration-time curve of imidapril and the peak plasma concentration of the active metabolite imidaprilat are decreased when imidapril is given together with digoxin. Although six ACE inhibitors (captopril, enalapril, fosinopril, lisinopril, quinapril and ramipril) have been approved for use in heart failure by the US Food and Drug Administration, an overview of 32 clinical trials of ACE inhibitors in heart failure showed that no significant heterogeneity in mortality was found among enalapril, ramipril, quinapril, captopril, lisinopril, benazepril, perindopril and cilazapril. Initiation of therapy with captopril, ramipril, and trandolapril at least 3 days after an acute MI resulted in all-cause mortality risk reductions of 18 to 27%. Captopril has been shown to have similar morbidity and mortality benefits to those of diuretics and beta-blockers in hypertensive patients. Captopril has been shown to delay the progression of diabetic nephropathy, and enalapril and lisinopril prevent the development of nephropathy in normoalbuminuric patients with diabetes. ACE inhibitors are generally characterised by flat dose-response curves. Lisinopril is the only ACE inhibitor that exhibits a linear dose-response curve. Despite the fact that most ACE inhibitors are recommended for once-daily administration, only fosinopril, ramipril, and trandolapril have trough-to-peak effect ratios in excess of 50%[5].

Absorption, Distribution and Excretion
The absorption rate is 60-75% on an empty stomach; food can reduce absorption by 25-40% (some evidence suggests this reduction is not clinically significant). Captopril is primarily excreted via the kidneys after metabolism. Over 95% of the dose is excreted by the kidneys, with 45-50% as the unchanged drug and the remainder as metabolites. In dogs, approximately 75% of the oral dose is absorbed, but food in the gastrointestinal tract reduces bioavailability by 30-40%. Captopril is distributed in most tissues (excluding the central nervous system), and in dogs, its plasma protein binding rate is 40%. In healthy individuals or hypertensive patients on an empty stomach, approximately 60-75% of orally administered captopril is rapidly absorbed from the gastrointestinal tract. Food may reduce captopril absorption by 25-40%, but there is evidence that this effect is not clinically significant. In one study, after a single oral dose of 100 mg captopril in fasting healthy subjects, the mean peak plasma concentration reached 800 ng/mL within 1 hour.
/Breast Milk/ The concentration of captopril in human breast milk is approximately one percent of the concentration in maternal blood.
For more complete data on the absorption, distribution, and excretion of captopril (7 items), please visit the HSDB records page.

---

Metabolism/Metabolites Hepatic metabolism. The main metabolites are captopril-cysteine disulfide and captopril disulfide dimer. Metabolites may undergo reversible interconversion.
Approximately half of the absorbed dose of captopril is rapidly metabolized, primarily as captopril-cysteine disulfide and captopril disulfide dimer. In vitro studies have shown that captopril and its metabolites may undergo reversible interconversion. Studies have shown that drug metabolism may be more extensive in patients with renal impairment than in patients with normal renal function.

---

Biological Half-Life
2 hours
A 43-year-old patient with mild heart failure attempted suicide by taking 5000 to 7500 mg of captopril. Blood pressure fluctuated around 100-120/50-75 mmHg, and the pulse did not show a tendency to increase (75-100 beats/min). …The calculated half-life of captopril was 4.4 hours. The half-life of captopril in dogs is approximately 2.8 hours. In patients with normal renal function, the elimination half-life of unmetabolized captopril appears to be less than 2 hours. The elimination half-life of captopril and its metabolites is related to creatinine clearance; in patients with creatinine clearance below 20 mL/min, the elimination half-life is prolonged to approximately 20-40 hours, while in anuric patients, the elimination half-life can be as long as 6.5 days. Absorption: The bioavailability of captopril (SQ-14534; SA333) in healthy volunteers is 60%–75%. Food intake reduces its absorption by about 30% (lower peak plasma concentration Cmax), so it is recommended to take it on an empty stomach. After oral administration of 50 mg, the peak plasma concentration (Cmax) reaches 1.2–1.8 μg/mL at 1 hour [5]
- Distribution: In healthy volunteers, the volume of distribution (Vd) of captopril (SQ-14534; SA333) is about 0.2 L/kg. It hardly crosses the blood-brain barrier, and the concentration in cerebrospinal fluid is less than 1% of the plasma concentration [5]
- Metabolism: Captopril (SQ-14534; SA333) is minimally metabolized in vivo (only about 10% of the dose is metabolized to inactive disulfide conjugates). No active metabolites were detected [5]
- Excretion: It is mainly excreted by the kidneys. Approximately 70%–80% of the oral dose is excreted unchanged in the urine within 24 hours. In healthy volunteers, the elimination half-life (t1/2) is 2–3 hours; in patients with severe renal impairment (creatinine clearance <30 mL/min), t1/2 is prolonged to 12–14 hours.[5]

Toxicity Summary
Identification and Uses: Captopril is an angiotensin-converting enzyme (ACE) inhibitor and an antihypertensive drug. Human Studies: Captopril prevents the conversion of angiotensin I to angiotensin II (a potent vasoconstrictor) by competing with its physiological substrate (angiotensin I) for the active site of ACE. The drug has approximately 30,000 times greater affinity for ACE than for angiotensin I. Inhibition of ACE reduces plasma angiotensin II concentrations, thereby partially lowering blood pressure by reducing vasoconstriction. Myelosuppression caused by captopril is rare, except in certain high-risk patient groups. Severe exfoliative rashes have also been associated with captopril. A 57-year-old male with mild renal impairment due to diabetic glomerulosclerosis developed acute renal failure shortly after starting captopril treatment for hypertension, accompanied by a generalized exfoliative rash and peripheral eosinophilia. Cholestatic jaundice is a rare complication of captopril use. The severity can range from histological cholestasis of the liver to apparent fulminant hepatic failure. There has been a reported case of a 75-year-old man committing suicide due to a captopril overdose. He ingested approximately 90 tablets of 12.5 mg captopril. Taking captopril for 3 months or longer can lead to zinc depletion in red blood cells. Hypoplasia (loss of taste) is one of the known side effects of captopril. Studies suggest that hypogustia may be associated with zinc deficiency. Fetal toxicity of captopril in the second and third trimesters is similar to other angiotensin-converting enzyme inhibitors. Use of this drug in the second and third trimesters may lead to teratogenicity and serious fetal and neonatal toxicity. Fetal toxicity may include anuria, oligohydramnios, fetal craniosynostosis, intrauterine growth restriction, preterm birth, and patent ductus arteriosus. Stillbirth or neonatal death may occur. Anuria-related oligohydramnios may lead to fetal limb contractures, craniofacial deformities, and pulmonary hypoplasia. Neonates exposed to captopril in utero may experience severe anuria and hypotension, unresponsive to vasopressors and volume expansion therapy. Close monitoring of neonatal renal function and blood pressure is essential. Mutagenicity studies of the fixed combination of captopril and hydrochlorothiazide have not been conducted, but the effects of the two components used alone in a 2:1 ratio have been investigated. In sister chromatid exchange assays of human lymphocytes, captopril/hydrochlorothiazide did not show mutagenicity or chromosomal breakage. Cytogenetic analysis of human lymphocytes exposed to captopril/hydrochlorothiazide at concentrations of 5, 25, and 50 μg/mL (total concentration of both drugs) after metabolic activation showed no consistent chromosomal abnormalities. Even when such abnormalities were observed, no concentration-responsiveness was observed. Animal studies: No carcinogenic effects were observed in rats or mice administered 50–1350 mg/kg captopril daily for 2 years. Reproductive studies in hamsters and rats using high doses of captopril also did not reveal teratogenic effects. However, this drug is embryolet-lethal and associated with a lower incidence of craniofacial malformations in rabbits, possibly due to a significant decrease in blood pressure in this species. Neonatal survival was reduced in offspring of mother mice continuously administered captopril during pregnancy and lactation; stillbirth rates in ewes have been reported to increase. Mutagenicity studies of the fixed combination of captopril and hydrochlorothiazide have not been conducted, but the effects of the two components used alone in a 2:1 ratio have been investigated. In vitro, captopril/hydrochlorothiazide did not show mutagenicity or chromosome breakage in the Salmonella Ames reversion assay, fissile yeast forward mutation assay, or Saccharomyces cerevisiae gene conversion assay, regardless of metabolic activation. In in vivo mouse micronucleus assays, no genotoxicity was found when captopril and hydrochlorothiazide were administered orally at a 2:1 ratio at a dose of 2,500 mg/kg (total concentration of both drugs). Ecotoxicity studies: Captopril can induce oxidative stress in carp (C. carpio).

---

Hepatotoxicity
As with other ACE inhibitors, captopril is associated with a low incidence of elevated serum transaminases (
Probability score: B (probably but rarely causes clinically significant liver injury)).

---

Effects during pregnancy and lactation
◉ Overview of use during lactation
Because captopril is present in low amounts in breast milk, the amount ingested by the infant is small and no adverse effects are expected on breastfed infants.
◉ Effects on breastfed infants
In a report involving 12 mothers, several mothers continued to breastfeed their infants while taking captopril 100 mg three times daily. No adverse reactions were observed in the infants. [1]
One woman was diagnosed with Cushing's disease during her pregnancy. Postpartum, she took metenprone 250 mg three times daily; bisoprolol 10 mg twice daily; and captopril 12.5 mg twice daily. She fed her premature infant with approximately 50% breast milk and 50% formula. Five weeks postpartum, the pediatric team considered the infant's growth and development to be normal. [3] ◉ Effects on lactation and breast milk In a series of controlled studies reported in a paper, captopril had no effect on the diurnal rhythm of prolactin, response to prolactin-inducing drugs, or serum prolactin levels in patients with prolactin-secreting tumors. [4] In a study of young hypertensive men, oral administration of 25 mg captopril significantly reduced serum prolactin levels 90 minutes after administration compared to placebo. [5] Maternal prolactin levels in established lactating mothers may not affect their ability to breastfeed. In one report, one of 12 subjects, a woman, was unable to produce enough milk for the study despite successfully breastfeeding for 6 months after taking 100 mg captopril three times daily. [1] It is unclear whether this reduction was due to the effect of captopril. Protein Binding: 25-30% binds to plasma proteins, primarily albumin. Interactions: This article reports a case of a 70-year-old male patient with hypertension who developed three nodular hemangioma-like lesions in his left arm after six years of treatment with captopril (Lopril) 75 mg/day and acebutolol hydrochloride (Shukert) 200 mg/day. The patient had no history of blood transfusions, intravenous medications, or opportunistic infections. Clinical and histopathological examination revealed typical Kaposi's sarcoma presentation. One month after discontinuing captopril, the Kaposi's sarcoma lesions began to regress; after three months, no lesions were observed. Biopsy showed residual features of Kaposi's sarcoma. However, it is unclear whether the development of Kaposi's sarcoma was due to captopril alone or through interaction with acebutolol hydrochloride. Concomitant oral administration of captopril and antacids may decrease the rate and extent of gastrointestinal absorption of captopril. A single oral dose of 50 mg captopril 15 minutes after administration of an antacid containing magnesium carbonate and aluminum hydroxide can reduce captopril bioavailability by 40-45% and delay and decrease peak serum concentrations. However, there is evidence that this potential interaction may not be clinically significant, but further investigation is needed. Neuropathy has been reported in two patients treated with captopril and cimetidine. However, further documentation of this potential interaction is required. In some diabetic patients, initiation of captopril treatment has been associated with unexplained hypoglycemia, in patients whose diabetes was previously controlled with insulin or oral hypoglycemic agents. Testing in these patients suggests that captopril may increase insulin sensitivity; the mechanism of this effect is unclear. The risk of inducing hypoglycemia should be considered when initiating captopril treatment in diabetic patients. More complete data on captopril interactions (22 in total) can be found on the HSDB documentation page.

---

Non-human toxicity values
Oral LD50 in rats: 4245 mg/kg
Oral LD50 in mice: 2500 mg/kg
Intravenous LD50 in mice: 663 mg/kg
Intravenous LD50 in rats: 554 mg/kg
For more complete non-human toxicity data for captopril (6 in total), please visit the HSDB records page.

[1]. Eritadenine from Edible Mushrooms Inhibits Activity of Angiotensin Converting Enzyme in Vitro. J Agric Food Chem. 2016;64(11):2263-2268.

[2]. Captopril/enalapril inhibit promiscuous esterase activity of carbonic anhydrase at micromolar concentrations: An in vitro study. Chem Biol Interact. 2017;265:24-35.

[3]. Simplified captopril analogues as NDM-1 inhibitors. Bioorg Med Chem Lett. 2014;24(1):386-389.

[4]. The molecular basis for the selection of captopril cis and trans conformations by angiotensin I converting enzyme. Bioorg Med Chem Lett, 2006. 16(19): p. 5084-7.

[5]. Song, J.C. and C.M. White, Clinical pharmacokinetics and selective pharmacodynamics of new angiotensin converting enzyme inhibitors: an update. Clin Pharmacokinet, 2002. 41(3): p. 207-24.

Therapeutic Uses
Angiotensin-converting enzyme inhibitors; antihypertensive drugs. ClinicalTrials.gov is a registry and results database that indexes 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 (for patient health information) and PubMed (for citations and abstracts of academic articles in the medical field). Captopril is indexed in the database. Captopril tablets are indicated for the treatment of hypertension. …Captopril tablets are effective when used alone or in combination with other antihypertensive drugs, especially thiazide diuretics. The antihypertensive effects of captopril and thiazide diuretics are roughly additive. /Included on US product label/
Captopril tablets are indicated for the treatment of congestive heart failure, usually used in combination with diuretics and digitalis. The benefit of captopril for heart failure does not necessarily require digitalis; however, most controlled clinical trial experience with captopril comes from patients receiving concurrent treatment with digitalis and diuretics. /Included on US product label/
For more complete data on the therapeutic uses of captopril (11 in total), please visit the HSDB record page.

---

Drug Warning
/Black Box Warning/ Warning: Fetal toxicity. If pregnancy is discovered, captopril tablets should be discontinued as soon as possible. Drugs that act directly on the renin-angiotensin system may cause harm or even death to the developing fetus. Most patients tolerate captopril well; however, rare reports of serious adverse reactions (e.g., neutropenia, agranulocytosis, proteinuria, aplastic anemia) have been observed, primarily in patients with renal insufficiency (especially those with collagen vascular disease). Adverse reactions to captopril usually resolve with dose reduction, and sometimes disappear even with continued treatment without dose reduction; they are usually reversible upon discontinuation. The most common adverse reactions to captopril are rash and loss of taste. Approximately 4–12% of patients experience adverse reactions requiring discontinuation of captopril. Captopril is contraindicated in patients with known hypersensitivity to captopril or other angiotensin-converting enzyme inhibitors (e.g., patients who have developed angioedema during treatment with other angiotensin-converting enzyme inhibitors). Patients taking captopril should be advised not to interrupt or discontinue treatment unless directed by their physician. Patients with congestive heart failure taking captopril should avoid rapid increases in physical activity.
For more complete (32) drug warnings for captopril, please visit the HSDB record page.

---

Pharmacodynamics
Captopril is an angiotensin-converting enzyme inhibitor that antagonizes the renin-angiotensin-aldosterone system (RAAS). The renin-angiotensin-aldosterone system (RAAS) is a mechanism for maintaining homeostasis, regulating 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 I (AT1), which is then cleaved by angiotensin-converting enzyme (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. Secondly, AT2 stimulates the posterior pituitary gland to secrete angiotensin (also known as antidiuretic hormone or ADH). Antidiuretic hormone (ADH) further stimulates the kidneys to reabsorb water by inserting aquaporin 2 (AQP2) channels into the apical membrane of distal convoluted tubules (DCT) and collecting duct cells. Thirdly, angiotensin II (ATII) raises blood pressure by directly constricting arteries. Stimulation of type I ATII receptors on vascular smooth muscle cells triggers a series of events that ultimately lead to muscle cell contraction and vasoconstriction. In addition to these major effects, ATII also induces a thirst response by stimulating hypothalamic neurons. Angiotensin-converting enzyme (ACE) inhibitors inhibit the rapid conversion of ATI to ATII and antagonize the blood pressure increase induced by the renin-angiotensin-aldosterone system (RAAS). ACE (also known as kallikrein II) is also involved in the enzymatic inactivation of bradykinin (a vasodilator). Inhibition of bradykinin inactivation increases bradykinin levels and maintains its effects by increasing vasodilation and lowering blood pressure. Captopril (SQ-14534; SA333) is the first oral angiotensin-converting enzyme inhibitor (ACEI) to be used clinically. It exerts its antihypertensive effect by inhibiting ACE, thereby reducing the conversion of angiotensin I to angiotensin II (a potent vasoconstrictor) [4][5]. 2. The thiol group of captopril (SQ-14534; SA333) is crucial for its binding to ACE: it forms a coordination bond with zinc ions at the active site of ACE, enhancing the binding affinity [4]. 3. Therapeutic indications include essential hypertension (monotherapy or combination therapy), congestive heart failure (in combination with diuretics), and diabetic nephropathy (for reducing proteinuria) [5].

C9H15NO3S

217.29

217.077

C, 49.75; H, 6.96; N, 6.45; O, 22.09; S, 14.76

62571-86-2

Captopril hydrochloride;198342-23-3;Captopril-d3;1356383-38-4

44093

White to off-white, crystalline powder
Crystals from ethyl acetate/hexane

1.3±0.1 g/cm3

427.0±40.0 °C at 760 mmHg

104-108 °C(lit.)

212.1±27.3 °C

0.0±2.2 mmHg at 25°C

1.551

0.27

2

4

3

14

244

2

S([H])C([H])([H])[C@@]([H])(C([H])([H])[H])C(N1C([H])([H])C([H])([H])C([H])([H])[C@@]1([H])C(=O)O[H])=O

FAKRSMQSSFJEIM-BQBZGAKWSA-N

InChI=1S/C9H15NO3S/c1-6(5-14)8(11)10-4-2-3-7(10)9(12)13/h6-7,14H,2-5H2,1H3,(H,12,13)/t6-,7-/m0/s1

(2S)-1-[(2S)-2-methyl-3-sulfanylpropanoyl]pyrrolidine-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: ≥ 2.5 mg/mL (11.51 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 25.0 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.

---

Solubility in Formulation 2: ≥ 2.5 mg/mL (11.51 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 25.0 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.

---

View More

Solubility in Formulation 3: ≥ 2.5 mg/mL (11.51 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 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

---

Solubility in Formulation 4: 32.5 mg/mL (149.57 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

---

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