Pharmacokinetics of Captopril in Healthy Subjects and in Patients with Cardiovascular Diseases

Abstract

Captopril, the first orally active inhibitor of angiotensin-converting enzyme, is used widely in the treatment of hypertension and congestive heart failure. The pharmacokinetics of this agent have been studied extensively in healthy subjects and in patients with hypertension, congestive heart failure, and chronic renal failure. Captopril contains a sulphydryl group and binds readily to albumin and other plasma proteins. The drug also forms mixed disulphides with endogenous thiol-containing compounds (cysteine, glutathione), as well as the disulphide dimer of the parent compound. These components in blood and urine are measured collectively as total captopril. Because of the reversibility of the formation of these inactive disulphides, total captopril may serve as a reservoir of the pharmacologically active moiety, and thus contribute to a duration of action longer than that predicted by blood concentrations of unchanged captopril. To measure free or unchanged captopril concentrations, a chemical stabiliser must be added to the biological samples to prevent the formation of captopril disulphides ex vivo. In healthy subjects given captopril intravenously, the body clearance of captopril and steady-state volume of distribution were about 0.7 L/h/kg and 0.8 L/kg, respectively. The elimination half-life of unchanged captopril was approximately 2 hours. The primary route of elimination of captopril is the kidney. The renal clearance of unchanged captopril exceeds the glomerular filtration rate, due to active tubular secretion of the drug. In healthy subjects, about 70 to 75% of an oral dose is absorbed and the bioavailability of captopril is approximately 65%. Peak blood concentrations are reached about 45 to 60 minutes after oral administration. The bioavailability of captopril is not altered by age or concomitant medications including diuretics, procainamide, allopurinol, cimetidine or digoxin. However, the co-administration of food or antacids, or probenecid with captopril has been shown to diminish the bioavailability of the latter and decrease its clearance, respectively. The decreased bioavailability of captopril when taken with meals does not significantly alter clinical responses to the drug. Over a wide range of oral (10 to 150 mg) and intravenous doses (2.5 to 10 mg) captopril had linear kinetics in healthy volunteers. In healthy subjects with normal renal function and patients with congestive heart failure given captopril 3 times daily, blood concentrations of total captopril accumulated, whereas those of unchanged captopril did not. Severe renal insufficiency was associated with an accumulation of both unchanged and total captopril.(ABSTRACT TRUNCATED AT 400 WORDS)

A new highly sensitive and specific overnight combined screening and diagnostic test for primary aldosteronism

“…Thus, captopril was administered to inhibit ACE activity, valsatan to counteract the remaining angiotensin activity at the receptor level, and dexamethasone to suppress the ACTH effect. The ACE inhibitor captopril was preferred because its rapid action within 60-90 min (16) and valsartan because of its high affinity to the ΑΤ-I receptor (17). Therefore, all participants received 2 mg dexamethasone, 50 mg captopril, and 320 mg valsartan at midnight, at least 2 h after the last meal the day before the early morning sampling for hormones' measurements to avoid the wellknown effect of food on these drugs adsorption.…”

Captopril inhibits angiogenesis and slows the growth of experimental tumors in rats.

“…3 A ). In patients taking captopril, plasma concentrations do not exceed 15 m (30). Even at these low concentrations, captopril was still a potent inhibitor of endothelial cell migration, exclusively blocking directional chemotaxis ( unshaded section of Fig.…”

Alteration of the erythrocyte glutathione redox balance by N‐acetylcysteine, captopril and exogenous glutathione

“…In vivo, NAC and captopril have a protective role in reperfusion injury [10,11,21]. It has been suggested that their beneficial action is due to their ability to scavenge oxygen radicals [20], thus reducing the stress on the cell and resulting in less oxidation of glutathione which is also a radical scavenger.…”

“…postulated that it is transported into the cytosol and deacetylated, thus providing more substrate for the enzyme y-glutamylcysteine synthetase and increasing the glutathione concentration in the cells [19,20]. In contrast, captopril has been found to cause an increase in intracellular glutathione oxidation in patients who responded to therapy, suggesting that it acts by facilitating direct oxidant scavenging, rather than by stimulating glutathione production [21]. Addition of exogenous reduced glutathione to human erythrocytes has been reported to stimulate the reduction of intracellular glutathione in a manner similar to NAC [22,23].…”